In his senior year, he completed 154 of 213 passes for 2,535 yards, 29 touchdowns, three interceptions, and was named as a National Football Foundation Hall of Fame Scholar-Athlete for Santa Clara County.

Edwards' best year was 2005, where he started all 11 games, completed 168 of 268 passes for 1934 yards and 17 touchdowns, leading the Cardinal to a 5–6 record.

[4] In 2006, Edwards was the starter for the first seven games, but suffered a season-ending broken foot against Arizona and relinquished the starting role to T. C. Ostrander.

In his first NFL start on September 30, 2007, against the New York Jets, he made 22 of 28 passes for 234 yards with a touchdown and an interception, leading the Bills to their first win of the season.

In his second start, against the Dallas Cowboys on Monday Night Football, Edwards completed 23 of 31 pass attempts for 176 yards and an interception as Buffalo narrowly lost 25–24.

In week 13, following a string of poor performances by Losman, Bills coach Dick Jauron named Edwards the starter against the Washington Redskins.

However, on the third play of the game Edwards suffered a concussion as a result of a hard hit by Adrian Wilson and did not return.

Fans began calling Edwards "Trent-ative" and "Captain Checkdown" due to his hesitation to throw the ball deep.

He did not play for the rest of the season except for making a brief appearance during the week 15 game against the New England Patriots when he spelled Fitzpatrick in the fourth quarter.

Edwards completed 1 of 2 passes for −1 yards before being carted off the field, injuring his right knee as a result of a sack by Patriots defender Tully Banta-Cain.

On his final play as a Bill, against Green Bay, Edwards ran out of bounds on a fourth down scramble, 7 yards short of the first down marker with 1:10 to go.

The Bills waived Edwards on September 27, one day after Fitzpatrick threw for 247 yards in a Week Three game against New England.

Edwards made his first appearance for the Jaguars on October 18, 2010, against the Tennessee Titans on Monday Night Football, when starting quarterback David Garrard left the game after suffering a concussion.

[23] After becoming a free agent following the 2010 season, Edwards signed with the Oakland Raiders on July 30, 2011, and was released on September 3, during the final roster cuts.

However, he started to warm up in training camp, and found his opportunity in the preseason, after quarterback Mike Kafka broke his non-throwing hand against the Pittsburgh Steelers.

The team cut Kafka on August 31, meaning Edwards had won the job as third-string quarterback, after the rookie Nick Foles.