Collins was a member of six NFL teams, most notably the Carolina Panthers, New York Giants, and Tennessee Titans.

In his second season, he helped the Panthers become the youngest NFL expansion team to clinch their division and appear in a conference championship, also earning him Pro Bowl honors.

Collins served as the Giants starting quarterback from 1999 to 2003, leading them to an appearance in Super Bowl XXXV.

Following a period of limited success, Collins earned a second Pro Bowl selection after helping the Titans obtain a league-best 13–3 record in 2008.

[2] As a senior quarterback in 1994, he was recognized as a consensus first-team All-American, having received first-team honors from the Associated Press, United Press International, The Football News, the Football Writers Association of America, the Walter Camp Foundation, and The Sporting News.

Collins was the linchpin of an explosive offense (including Ki-Jana Carter, Kyle Brady, and Bobby Engram) that shattered 14 school records and led the nation in scoring (47.8 ppg.)

With Collins at quarterback, the 1994 Nittany Lions completed an undefeated season, the fifth under coach Joe Paterno, capped by a Rose Bowl win over Pac-10 Champion Oregon.

His TD:INT ratio and completion percentage were less impressive, however, resulting in passer ratings of 73.8 and 75.3 for the regular season and postseason.

In the 2000 season, Collins led the Giants to Super Bowl XXXV, where they lost to the Baltimore Ravens.

[16] The team had already signed former league MVP Kurt Warner and traded for 2004's #1 draft pick, Eli Manning.

After two seasons and a 7–21 record with the Raiders, Collins was cut on March 10, 2006, in what was at least partially a move designed to free space with the salary cap.

After three games, all losses for the Titans, Collins had completed fewer than half his passes, and had thrown one touchdown and six interceptions.

After Young was injured against Jacksonville on September 7, 2008, Collins finished the game and was named the Titans' starting quarterback for the rest of 2008, later that week.

[22] Collins replaced Jets quarterback Brett Favre in the 2009 Pro Bowl, after first alternate Philip Rivers pulled out.

[25] After that loss and an 0–6 record on the season, coach Jeff Fisher replaced Collins as starting quarterback with Vince Young, three days before the November 1, 2009, game against the Jacksonville Jaguars.

Fisher stated that he was against this decision, saying that the problems with the team were unrelated to quarterback play, but he made the substitution after being urged by Titans owner Bud Adams to do so.

[28] On August 24, 2011, Collins decided to forgo his retirement plans and agreed with the Indianapolis Colts on a contract deal.

The Colts named Collins the starter for week one, ending Manning's streak of 227 consecutive starts (208 regular season plus 19 playoff games) and making Collins the first quarterback other than Manning to start a regular-season game for the Colts since Jim Harbaugh in week 17 of the 1997 NFL season.

Collins was selected by the Detroit Tigers in the 26th round of the 1990 MLB draft, but opted to attend Penn State.

[35] Before the 1997 season got underway, Collins's private battle with alcoholism started to make public headlines.

As a member of the Tennessee Titans, he readdressed the 1997 racial slur incident, explaining that "The guys were talking to each other that way, and I was trying to be funny and thought I could do it, too.