In 1995 at age 17, Piquionne played in the youth teams of Paris FC at Charenton. Not really convincing, he left the city to settle in Martinique, in Fort-de-France. There, he played football in the Division d’Honneur for amateur club Golden Star and then joined JS Morne Blanc. For three years he worked as a shoe salesman in a store located in downtown Fort-de-France.

On 31 January 2007, Piquionne moved to Monaco on loan. The contract included an option to purchase, valued at €6 million. On 3 February 2007, he played his first Ligue 1 match for Monaco, against Auxerre. At the end of the season, Monaco remained in Ligue 1 and despite his disappointing performances, they exercised their buyout clause. On 10 November 2007, he played his 200th match in Ligue 1, against Strasbourg at the Stade Louis-II (3-0).

Instead of representing FIFA member New Caledonia in Oceania, Piquionne represented Martinique. He may have been called during the 2003 CONCACAF Gold Cup qualification but he did not play the final tournament. As Martinique is not a member of FIFA, he was eligible to play for France for whom he was called up in a squad to play Lithuania on 24 March 2007 in a Euro 2008 qualifying match, but did not play. He made his international debut for France in a friendly against Austria on 28 March 2007, coming on as a substitute in the 78th minute for Abou Diaby at the Stade de France. He played for France B against Slovakia in August 2007, but never represented the senior team again.

On 29 July 2008, after a friendly match at Annecy, Piquionne signed a four-year deal for €4.5 million with Lyon. He wore the number 39 shirt and scored his first goal in the UEFA Champions League against Fiorentina.

On 5 August 2009, it was confirmed that Piquionne would join English Premier League club Portsmouth on a season-long loan. On his Pompey debut, against Rangers at Fratton Park in a friendly, he scored two goals in a 2–0 win. Piquionne made his first Premier League start for Portsmouth on 15 August 2009, a 0–1 loss to Fulham on the first day of the season. His first competitive goal for Portsmouth came in a 4–1 League Cup win against Hereford United on 25 August 2009. He scored his first Premier League goal four days later in another 4–0 win, this time at home to Wigan Athletic. Piquionne scored 11 goals in all competitions during his stint at Portsmouth, including scoring two goals against Birmingham City in the FA Cup to ensure Portsmouth progressed to the FA Cup semi-finals. On 11 April 2010, Piquionne scored the first goal in a 2–0 win over Tottenham Hotspur to send Portsmouth into the FA Cup final for the second time in three seasons. His goalscoring form at Portsmouth led Piquionne to feel as though he had finally found his feet in English football despite enduring a patchy start to his Premier League career.

On 16 July 2010, Piquionne joined West Ham United, managed by his former manager at Portsmouth, Avram Grant, for a €1.2 million transfer fee and a €450,000 bonus. He signed a three-year contract, becoming West Ham’s third summer signing. He made his Premier League debut with West Ham on 14 August in a 3–0 loss to Aston Villa, coming on as a second-half substitute for Radoslav Kováč. He scored his first goal for West Ham in a 2–1 win against Sunderland in the third round of the League Cup at the Stadium of Light on 21 September 2010. He scored his first Premier League goal for West Ham in a 1–0 win against local rivals Tottenham on 25 September 2010. This goal was also the 10,000th goal scored in the Premier League with a Nike-manufactured football. Piquionne was sent off in a vital Premier League game against Everton for taking his shirt off after scoring to put the Hammers 2–1 up in the 86th minute; Everton later scored to draw the match 2–2 and West Ham were relegated to the Championship at the end of the season.

On 6 March 2012, Piquionne was loaned by West Ham to fellow Championship side Doncaster Rovers on an initial one-month loan. On the same day, he made his debut in a 2–1 away win against Nottingham Forest, scoring his first goal with a 30-yard shot to put Rovers 1–0 ahead. He played eight games for Doncaster, scoring two goals and at the end of the season returned to West Ham as Doncaster were relegated to League One.

Piquionne left England to join Major League Soccer (MLS) side Portland Timbers in the United States. He signed a one-year contract on 28 February 2013. Piquionne made his debut for Portland on 16 March 2013, coming on as a substitute against rivals Seattle Sounders FC at CenturyLink Field. On 29 May 2013, he scored four goals in the first half of a US Open Cup match against the USL Pro team Wilmington Hammerheads. He re-signed for the Timbers on 7 January 2014, but was waived from the team’s roster on 13 May 2014.

On 4 August 2014, Piquionne returned to France to sign with Créteil in Ligue 2 for the 2014–15 season.

In July 2015, Indian Super League club Mumbai City confirmed the signing of Piquionne for the upcoming season. The club, then managed by Peter Reid, had also signed Cristian Bustos and Frantz Bertin, and featured Nicolas Anelka as player-coach. He scored three goals in his 12 appearances for the club.

Following his departure from Mumbai City and retirement from playing, Piquionne returned to Creteil as a coach in January 2016. He worked as a pundit for Canal+ during the 2016 Summer Olympics.