Oswalt was spotted by only one MLB scout, James Farrar of the Houston Astros. Convinced that Oswalt’s anonymity kept him hidden from other teams, the Astros allowed him to drop into the 23rd round of the 1996 MLB draft. By this point, Oswalt had drawn the attention of the Mississippi State Bulldogs, for whom he had long wanted play. The Astros enticed Oswalt with a $500,000 signing bonus, and he signed with the club on May 18, 1997. Oswalt would eventually become the latest-drafted player to lead his draft class in career Baseball-Reference Wins Above Replacement as of 2019.

In 1997, Oswalt played rookie ball in the Gulf Coast League, where he gave up only two runs in five starts. He was then called up to the Auburn Doubledays of the New York–Penn League, where he went 2–4 the rest of the way.

Oswalt split 1998 between the same two teams. In 16 innings of work with the Gulf Coast Astros, he struck out 27 batters and walked just one. Oswalt was promoted again to Auburn, where he recorded the league’s fourth-lowest ERA (2.18).

In 1999, when Oswalt was with the Class A Michigan Battle Cats in the Midwest League, he suffered an apparently serious shoulder injury. After a month of pain in his upper shoulder, Oswalt was convinced that his shoulder was torn. Shortly thereafter, he was checking the spark plug wires on his pickup truck. He touched one of the spark plug wires, causing the truck’s engine to start. The truck’s electric current flowed through Oswalt’s body, and consequently the muscles in his hand tightened on the spark plug wire. Unable to let go of it, Oswalt grasped the wire for almost one minute. Oswalt then claimed his foot slipped off the truck’s bumper and he was finally “thrown off.” “My truck done shocked the fire out of me, and my arm don’t hurt no more.” Apparently, the electric charge loosened accumulated scar tissue in the shoulder. Oswalt claims he has not felt any pain in his shoulder since the incident. He finished 1999 with 143 strikeouts and a club-high 13 wins.

Oswalt began 2000 with the Class A Kissimmee Cobras of the Florida State League, going 4–3 with a 2.98 ERA before a player injury on Class AA Round Rock Express of the Texas League led to his promotion. Oswalt was only expected to pitch a few games and had been given a round-trip ticket. But after striking out 15 batters in his first start with the Express, manager Jackie Moore tore up his ticket. Nolan Ryan, owner of the Express and Oswalt’s idol, admired his calm demeanor and his aggressiveness so much that he successfully lobbied to keep Oswalt on the roster, where he would go 11–4 with a 1.94 ERA, and recording 141 strikeouts over 19 games (18 starts). It was here that he met pitching coach Mike Maddux, who counseled the young Oswalt to be economical in his pitch selection by throwing more breaking balls and inducing groundouts early in the count.

In 2001, Oswalt started the season with the Triple-A New Orleans Zephyrs, where he went 2–3 before being called up to the MLB when left-hander Wayne Franklin was optioned down.

Oswalt finished his rookie campaign in 2001 with a 14–3 record and a 2.73 ERA, including a 12–2 mark with a 2.82 ERA in his 20 starts. He finished second in voting for National League Rookie of the Year, losing unanimously to Albert Pujols. He also placed fifth in Cy Young Award voting, which was won by Randy Johnson. He won the Sporting News NL Rookie Pitcher of the Year Award. He pitched 24 consecutive scoreless innings before giving up a home run to Andrés Galarraga of the San Francisco Giants.

The 2002 season was another step forward for Oswalt, who finished the season with a 19–9 record, striking out a career-high 208 batters and finishing with an ERA of 3.01. He tied with Éric Gagné for fourth in Cy Young voting, losing once again to Johnson. From July 27 to September 8, he won a then-club record 9 straight starts before getting a no-decision in an extra innings’ Astros loss to the St. Louis Cardinals.

Injuries plagued Oswalt in 2003, but he still recorded a 10–5 record over 21 starts. He started a team no-hitter against the New York Yankees on June 11. Oswalt left after one inning, and 5 more Astros continued to no-hit the Yankees.

He rebounded in 2004 with the first 20-win season of his career, the only National League (NL) pitcher to do so that year. He went 20–10 despite a career-high 3.49 ERA, and struck out 206 batters. He finished third in Cy Young Award voting, behind his teammate Roger Clemens and, once again, Randy Johnson. He also made his first postseason appearance, going 1–0 with a 4.19 ERA in three starts and one relief appearance. He threw two complete-game shutouts during the season, both against the Milwaukee Brewers. He led all NL starters with the fastest average fastball, at 94.0 miles per hour (151.3 km/h). He won the Darryl Kile Award.

In 2005, Oswalt threw a career-high 241⁄3 innings, striking out 184 batters and only walking 48 on the way to his second consecutive 20-win season — the first Astro to do so since Joe Niekro in 1979–80. He notched a 20–12 record, including a career-best 10-game winning streak from April 10 to July 26, with a 2.94 ERA, and was named to his first Major League Baseball All-Star Game as the National League All-Star Final Vote winner. He was fourth in Cy Young Award balloting, won by Chris Carpenter. In the postseason that year, Oswalt started 4 games and went 3–0. His two seven inning one-run performances netted him the NLCS MVP award, including a three-hit seven strikeout game in Game 6.

Oswalt went 15–8 in 2006 and was named to his second consecutive All-Star team and his final ERA led NL (2.94), and also struck out 166 batters while walking 38. On August 29, 2006, Oswalt’s 29th birthday, he signed a five-year extension with the Astros totaling $73 million with an option for a 6th year. He again finished fourth in Cy Young Award voting, won by Brandon Webb. On September 18, while pitching against the Cincinnati Reds, Oswalt recorded his 1,000th strikeout, becoming the eighth player in Astros history to reach the milestone.

Before the 2007 season, Roy Oswalt received the second-highest Pitcher Player Value Ranking from Sports Illustrated Baseball Preview Edition. He was rated the best in the NL ahead of Brandon Webb and Chris Carpenter, and was only below the 2006 Triple Crown winner Johan Santana. On July 5, 2007, it was announced Oswalt would replace an injured John Smoltz on the National League All-Star team, making it Oswalt’s third consecutive All-Star game appearance. He did not pitch in the All-Star Game, however. On August 13, 2007, Sports Illustrated named Oswalt as one of the top five pitchers (along with Santana, Roy Halladay, Jake Peavy, and Justin Verlander). On September 26, 2007, it was reported that Oswalt was suffering from pain in his left side and it was decided to shut him down for the remainder of the season so as not to risk a more serious injury. He finished the 2007 season throwing 212 innings, his fourth consecutive year of 200 or more innings pitched, a 14–7 record, an ERA of 3.18 and 154 strikeouts.

In 2009, Oswalt played for the United States in the World Baseball Classic, appearing in two games. He was the winning pitcher in the contest versus the Netherlands, but was pulled from the semifinal against Japan in the fourth inning after giving up 6 runs.

In the 2010 NLDS, Oswalt pitched Game 2 of the Phillies’ three-game sweep of the Cincinnati Reds; he gave up 4 runs in 5 innings, but the Phillies came back to win 7–4. In the 2010 NLCS against the San Francisco Giants, Oswalt won Game 2 by allowing only 1 run in 8 innings, which was his ninth postseason start without a loss. Oswalt entered Game 4 in the bottom of the ninth inning, attempting to preserve a tie game, but took the loss. In Game 6, Oswalt allowed 2 runs in 6 innings but left with the game tied; the Giants later broke the tie to win that game and the series.

Oswalt’s repertoire and approach evolved over time. His changeup was originally a rarely used circle change. However, in 2010, he changed the grip to make it more similar to a “fosh” grip. Originally a fastball-curveball pitcher, Oswalt made his changeup part of his standard repertoire. He threw it only 4% of the time in 2008, but that jumped to 19% by 2011. He says it also helped compensate for slightly reduced fastball velocity as a result of his age.

After a strong start to the 2011 season, Oswalt took a leave of absence from the Phillies on April 27, 2011, citing “personal reasons”, namely to check on his family and home after a series of devastating tornadoes in Mississippi. He later spent several weeks on the disabled list due to a back injury. Overall, his season was considered to be disappointing, perhaps due to his back problems.

In the 2011 NLDS, Oswalt started Game 4 with the Phillies leading the St. Louis Cardinals 2 games to 1 and needing only one more win to advance. Oswalt allowed 5 runs in 6 innings and took the loss. The Phillies also lost Game 5 and were eliminated from the playoffs.

After the 2011 season for the Phillies, the team declined his option, thus making him a free agent.

Oswalt was regarded as one of the top starters on the free agent market and was courted by several teams. ESPN’s Jayson Stark reported that Oswalt, only 34 years old and up to that point an elite pitcher, was holding out for the hope of a large salary from a team relatively close to his hometown of Weir, Mississippi. However, several of the teams on Oswalt’s list were not interested, and Stark reported that Oswalt’s performance in 2011 prevented other teams from offering the money he expected.

Oswalt agreed to a minor league deal with the Colorado Rockies on May 2, 2013. He made his Rockies debut on June 20 against the Washington Nationals, pitching 5 innings and giving up 4 earned runs on 9 hits with 11 strikeouts.

Oswalt retired after the 2013 season and went to work for his former agent. Oswalt, along with former teammate Lance Berkman signed a one-day contract with Houston to officially retire as an Astro on April 5, 2014.

Oswalt was first eligible for the Baseball Hall of Fame in 2019. He received 4 votes, or 0.9%, which is less than the 5% threshold and thus became ineligible for further consideration. Oswalt was inducted into the Mississippi Sports Hall of Fame on August 3, 2019.