In 2006, Ponder sat out his true freshman season at Florida State on redshirt status. In 2007, he served as the back-up behind starting quarterback Drew Weatherford. Ponder saw action against Virginia Tech when Weatherford was taken out of the game due to an injury in the second quarter. Although Florida State lost, 40–21, Ponder completed eight out of 18 passing attempts for 105 yards and one touchdown.
Before the 2008 season, Ponder was named the starting quarterback ahead of senior Weatherford. The Miami Herald said that the decision showed the coaching staff put "a premium on mobility over maturity." Ponder started in all 13 games, and completed 177 passes on 318 attempts for 2,006 yards, 14 touchdowns, and 13 interceptions. He also made 119 rushing attempts for 423 yards and four touchdowns. The Seminoles finished the season with a 9–4 record, including a victory over Wisconsin in the Champs Sports Bowl. At season's end, Ponder was named the team's most valuable offensive player.
In 2009, Ponder was well on his way to a career season when he suffered a season ending shoulder injury at Clemson. Through the first eight games of the season, he led the ACC in passing average per game and was one of the national leaders in yards and passing efficiency. He threw for over 2,700 yards and 14 touchdowns and considered jumping to the NFL a year early. However, after hitting Clemson safety DeAndre McDaniel on an interception return, Ponder separated his shoulder and missed the rest of the season. This ended his professional hopes, at least for one year. He resumed his role as the starting quarterback in 2010.
Before the 2010 season, Ponder was named to the Maxwell Award watch list. Florida State launched a campaign promoting Ponder as a Heisman Trophy candidate in July 2010. During the 2010 season, Ponder battled numerous setbacks to his health, including a swollen bursa sac in his throwing elbow. He re-injured the elbow numerous times during the season, and had to have it drained three times.
The 2010 season, Ponder's senior year and only year under coach Jimbo Fisher, had seen the greatest amount of success for the quarterback. Ponder was the first Seminole quarterback since Chris Weinke in 1999 to lead his team to victories over both its in-state rivals, Miami and Florida. He also won the 2010 James Tatum award, given to the nation's top student-athlete, and a National Football Foundation Scholar-Athlete Award. Ponder graduated from Florida State in two and a half years with a degree in finance and a 3.73 GPA, then an MBA, and is studying for his second graduate degree, in sports management. At the 2011 Under Armour Senior Bowl, Ponder won MVP honors after throwing for 2 TD's and leading the South to a win over the heavily favored North.
Ponder was selected 12th overall by the Minnesota Vikings in the first round of the 2011 NFL Draft. Ponder announced in his introduction press conference that he intended to wear jersey number 7 in the NFL. He made his NFL debut against the Chicago Bears in the fourth quarter on October 16, 2011. It was announced on Tuesday, October 18, that he would make his first start the following Sunday against the Green Bay Packers. On Ponder's first career pass attempt as a starter he hit Michael Jenkins on a 72 yard play-action pass. Two plays later, he hit Visanthe Shiancoe in the end zone on another playaction pass. He finished the game 13 of 32 for 219 yards with 2 TDs and 2 INTs in the 33-27 loss. Ponder was able to get his first win as an NFL starting quarterback with the Minnesota Vikings the following week against Cam Newton and the Carolina Panthers on October 30, 2011. He threw for 236 yards and a touchdown, and had a passer rating of 102.7. After a bye week, the Vikings faced off against the Packers again, this time on Monday Night Football at Lambeau Field. Ponder didn't perform as well as he did the first time around, and the Vikings were blown out 45-7. He threw two touchdowns and three interceptions against the Oakland Raiders in a losing effort. Ponder began to struggle down the stretch of his rookie campaign, losing games to the Atlanta Falcons, and the Denver Broncos. In the game against the Broncos, he threw a crucial interception late in the fourth quarter to set up Tim Tebow and the Broncos for a game-winning drive. The next week, Ponder was injured in a game against the rival Detroit Lions at Ford Field. Backup quarterback Joe Webb nearly brought Minnesota to a victory. After a loss to the NFC South champion New Orleans Saints, Ponder was injured in each of the final two regular season games, at the Washington Redskins and in the season finale against the Chicago Bears. Ponder finished the season throwing 13 touchdown passes and 13 interceptions. In the 2012 season through his first five games, he threw for 7 touchdowns and 0 interceptions. Ponder would lead the Vikings to the playoffs that year with 18 touchdowns and 12 interceptions.
Ponder returned for the Week 1 game of the season at the Lions when the young QB threw 18/28 for 236 yards, but with a touchdown and 3 interceptions and also lost a fumble in the 34-24 loss. In Week 2, Ponder threw 16/30 for 227 yards with a touchdown and an interception in a heartbreaking 31-30 loss at the Bears. For their home opener in Week 3 against the Browns, they surprisingly lost as Ponder went 25/42 for 228 yards, but threw an interception. Also he would rush for 42 yards and 2 touchdowns in the 31-27 loss.