At Tulane after redshirting for the 2008 season, Ryan Griffin played in nine games of the 2009 season. He led the team in total offense, passing attempts, completions, passing yards, and touchdown passes, while finishing 2nd in completion percentage and passing efficiency. All of his offensive numbers stand as Tulane records for a freshman quarterback. Griffin started all 11 games he played in as a sophomore in the 2010 season, and ranked 6th in Conference USAin passing yards per game, 8th in total offensive yards per game, and 10th in passing efficiency. He gained more than 300 yards in 3 games, including a season-best 412 yards against Tulsa. In the 2011 season, he started all 13 games and once again led the team in total offense, pass attempts, completions, passing yards, touchdown passes, and passing efficiency. As a senior in the 2012 season, he started all nine games he played in and was given an honorable-mention spot on the All-Conference USA team. He finished the season ranked 2nd in C-USA in passing yards per game and yards of total offense per game, and 5th in passing efficiency. Griffin threw for 300-plus yards 5 times with two 400-plus yard games, and twice set the school single-game passing record. He set the record the first time with 466 yards and a career-best 5 touchdown passes vs UAB and surpassed that with 476 yards and 4 touchdowns vs Rice. Griffin holds the Tulane career records in pass attempts, completions, and completion percentage. He is 2nd in passing yards, passing yards per game, pass attempts per game, completions per game, and 300-yard passing games. Griffin finished his college career with 9,026 yards, 56 touchdowns, and 35 interceptions.
Griffin signed with the New Orleans Saints as an undrafted free agent following the 2013 NFL Draft. He was released on August 31, 2013. On September 1, 2013, Griffin re-signed to the Saints' Practice Squad. He was placed on the active roster on October 22, 2013, only after the St. Louis Rams offered Griffin an opportunity to sign with them. To facilitate Griffin's signing to the active roster, linebacker Martez Wilson was waived. On September 2, 2014, it was announced that the Saints had waived Griffin and re-signed kicker Shayne Graham to the 53-man roster. After clearing waivers on September 3, 2014, Griffin was re-signed to the Saints practice squad. To make room for Griffin, linebacker Todd Davis was released from the practice squad. Griffin was released on September 5, 2015, for final roster cuts before the start of the season.
On September 6, 2015, Griffin was claimed off waivers by the Buccaneers. In 2015 and 2016, Griffin was the Buccaneers' third-string quarterback behind Jameis Winston and Mike Glennon, and did not see any game action. On August 30, 2017, Griffin signed a one-year contract extension with the Buccaneers. He was placed on injured reserve on September 4, 2017, after suffering a shoulder injury in the preseason. He was activated off injured reserve to the active roster on November 7, 2017, to back up Ryan Fitzpatrick after starter Winston was sidelined with an injury. On March 12, 2019, Griffin signed a two-year contract extension with the Buccaneers. In Week 14 of the 2019 season against the Indianapolis Colts, he made his NFL debut, starting the second half for the Buccaneers as Winston suffered a hand injury late in the second quarter. Griffin completed 2 of 4 passes for 18 yards on a 6-play drive that resulted in a Bradley Pinion punt. Winston returned to the game on the next Buccaneers possession and finished the game for a 38–35 victory.
