Francisco spent 2007 with the single-A Dayton Dragons. He hit .268 in 534 at-bats, slugging 25 home runs and driving in 90. Juan was a Midwest League mid-season All-Star and post-season All-Star for the Dragons.

Promoted again in 2008, this time to the single-A advanced Sarasota Reds, he again spent the entire season with the same team. In 516 at-bats, he hit .277 with 23 homers and 92 RBI. Francisco earned All-Star status again, for both the mid-season and post-season in the Florida State League. In addition, he was selected to play in the 2008 Major League Baseball All-Star Futures Game. Francisco was named Reds’ Minor League Hitter of the Year for 2008. Juan played winter ball for Gigantes del Cibao of the Dominican Winter Baseball League. In 40 games for the team, he .360 with 37 RBI, and his 12 home runs set the DWL record for regular season homers by a left-handed hitter. He continued to produce in the playoffs, hitting six more homers and 18 more RBI. His performance earned him the DWL Rookie of the Year accolade. He was added to the 40-man roster on November 20.

Originally a switch-hitter, Francisco abandoned hitting right-handed in 2009 to become a full-time lefty.

Francisco made his debut for the Reds as part of a 3–1 win over the Houston Astros on September 14, 2009 at Great American Ball Park. Pinch hitting for left fielder Darnell McDonald in the seventh inning, Francisco faced pitcher Jeff Fulchino and struck out in his first Major League at bat. He finished his September call-up batting .429 (9-for-21) with his first career big-league homer and seven RBI.

Francisco spent 2010 mainly with the Louisville Bats. Ironically, in his best statistical season to date, he was not named to any All-Star roster for the first time in four years. For the Bats, he played in 77 games and hit .286 in 308 at-bats, slugging 18 homers and 59 RBI in his shortened season. He spent the rest of the season with the Reds, and saw action in 36 games. He hit .273 with one homer and seven RBI in 55 at-bats.

Francisco made the club out of spring training in 2011 as a backup to Scott Rolen, backup left fielder, and a left-handed bat off the bench. He switched his number from 64 to the more conventional number 25. On September 12, 2011, Francisco hit a home run off Chicago Cubs pitcher Rodrigo López that cleared the right field bleachers at Great American Ball Park. It was estimated to have gone 502 feet. It was the second longest home run in Great American Ballpark history behind Adam Dunn’s 535 ft home run in 2004.

On April 1, 2012, Francisco was traded to the Atlanta Braves for pitcher J. J. Hoover. His debut for the Braves came at third base on April 7, 2012 against the New York Mets.

Francisco entered 2013 as the replacement for the recently retired Chipper Jones at third base, along with Chris Johnson. On April 16, 2013, Francisco had his first career multi-homer game in a 6–3 win over the Kansas City Royals. On May 8, Francisco hit his first career grand slam against Reds pitcher J. J. Hoover (who he had been traded for). Francisco was designated for assignment by the Braves on May 30 to make room on the roster for Alex Wood. At that point, Johnson won the starting third base job for himself. In 35 games with Atlanta, Francisco hit .241/.287/.398 with 5 HR and 16 RBI.

On June 3, 2013, Francisco was traded by the Braves to the Milwaukee Brewers for minor league pitcher Tom Keeling. He split first base duties with Yuniesky Betancourt until around mid-August, when Jonathan Lucroy and Sean Halton got more starts, with Francisco getting the smallest third, being used more often as a pinch-hitter. In 124 total games, he hit .227/.296/.412 with 18 HR and 48 RBI. He was released on March 24, 2014.

On April 1, 2014, the Toronto Blue Jays signed Francisco to a minor league contract, and assigned him to the Triple-A Buffalo Bisons. His contract was purchased by the Blue Jays on April 19, when Maicer Izturis was transferred to the 60-day disabled list, and he made his Blue Jays debut that day as the designated hitter. Francisco enjoyed early success as a member of the Blue Jays, but his inability to hit the breaking ball reduced his effectiveness, and then his playing time. He finished the 2014 season batting .220 with 16 home runs and 43 RBI, but struck out 116 times in 287 at-bats.

On November 19, 2014, Francisco was claimed off waivers by the Boston Red Sox. He was designated for assignment on November 25, but was non-tendered and became a free agent.

On January 10, 2015, Francisco signed a minor league deal with the Tampa Bay Rays. After failing to make the 25-man roster out of spring training, Tampa Bay attempted to send Francisco to Triple-A Durham Bulls, however he exercised an opt-out clause in his contract on April 5 and became a free agent.

On April 21, 2015, Francisco signed with the Yomiuri Giants of Nippon Professional Baseball. His NPB debut against the Hanshin Tigers took place on May 2. Francisco hit an RBI single that helped the Giants win a 1–0 shutout.

After sitting out the 2016 season, Francisco signed a minor league contract with the Baltimore Orioles in February 2017. He was released on May 16, 2017.

On June 6, 2017, Francisco signed with the Leones de Yucatán of the Mexican League.

On January 31, 2020, Francisco signed with the Guerreros de Oaxaca of the Mexican League. Francisco was released on June 5, 2020.