He played college football for the South Florida Bulls and was selected by the New York Giants in the first round of the 2010 NFL draft.

Pierre-Paul was born in Deerfield Beach, Florida, to Haitian immigrants Jean and Marie, who arrived in the United States in 1983.

In 2009, he played thirteen games for the Bulls with seven starts and totaled 45 tackles (16.5 for losses), 6.5 sacks, one interception (returned 18 yards for a touchdown), broke up three passes, and forced two fumbles.

[7] He made his NFL debut on September 12, 2010, in the New York Giants' season opener, and recorded two tackles.

[10] Pierre-Paul became the first player in NFL history to record a sack, forced fumble, and blocked field goal in the same game.

[14] Pierre-Paul played a big role in the Giants' playoff run where they competed against the New England Patriots in Super Bowl XLVI and won by a score of 21–17.

[22] Against the Green Bay Packers, he intercepted a pass by Scott Tolzien, which he returned for a touchdown in the 27–13 victory.

Reports indicated that the tag was non-exclusive, which meant that Pierre-Paul could negotiate with other teams, and the Giants had the right to match any offer or receive two first-round picks as compensation.

[32] Before the 2016 season, Pierre-Paul underwent further surgery on his hand which allowed him to wear a glove instead of the cumbersome club which he wore in 2015.

[33] In Week 12, he registered three sacks including a fumble that he returned 43 yards for his third career touchdown against the Cleveland Browns in a 27–13 win.

[34] On December 7, 2016, he underwent surgery for a sports hernia and was expected to be out six weeks but ended up missing the rest of the season due to the Giants losing in the Wild Card Round of the 2016–17 NFL playoffs to the Packers.

Without Pierre-Paul and injured cornerback Dominique Rodgers-Cromartie, the Giants allowed a season-high 38 points en route to a 38–13 loss.

[41] In May 2019, Pierre-Paul was involved in a single-car accident and experienced a neck fracture due to not wearing a seatbelt that put his season in jeopardy.

[44] In Week 12 against the Atlanta Falcons, Pierre-Paul recorded a strip sack on quarterback Matt Ryan which was returned by teammate Ndamukong Suh for an 11-yard touchdown in the 35–22 win.

[45] In Week 16 during a 23–20 loss to the Houston Texans, Pierre-Paul sacked quarterback Deshaun Watson three times.

[47] Overall, Pierre-Paul finished the 2019 season with 27 total tackles, 8.5 sacks, two passes defended, and two forced fumbles in ten games.

[53] In Week 11, during a 27–24 loss to the Los Angeles Rams, Pierre-Paul recorded six total tackles, two pass deflections, and an interception.