He played college football for the Utah Utes, where he earned consensus All-American honors in 2006, and was selected by the San Diego Chargers in the second round of the 2007 NFL draft.

Nearing the end of an electrifying senior year, Doug Robinson of the Deseret Morning News wrote an article championing Weddle for the Heisman Trophy based on how valuable he is to the Utah Utes.

Robinson wrote that Fisher DeBerry, Air Force's football head coach told Weddle after the game, "They're cheating you, son; they ought to give you two scholarships."

Head coach Norv Turner officially named Weddle the backup strong safety to begin the regular season, behind Clinton Hart.

[18] Weddle made his first NFL start in the season-opener against the Carolina Panthers and recorded a season-high 11 combined tackles (seven solo) and deflected a pass in their 26–24 loss.

On December 28, 2008, Weddle tied his season-high of 11 combined tackles (ten solo) and broke up a pass in a 52–21 win against the Denver Broncos in Week 17.

On January 3, 2009, Weddle made seven combined tackles and three pass deflections in the Chargers' 23–17 victory against the Indianapolis Colts in the AFC Wildcard Game.

[19] The following week, he collected 11 combined tackles (nine solo) and sacked Ben Roethlisberger during a 35–24 loss at the Pittsburgh Steelers in the AFC Divisional Round.

[22] Weddle intercepted a pass by quarterback Chad Henne, that was intended for wide receiver Davone Bess, and returned it for a 31-yard touchdown in the fourth quarter.

[26] On November 28, 2010, Weddle recorded four solo tackles, a season-high two pass deflections, and returned an interception for a touchdown during a 36–14 victory at the Indianapolis Colts in Week 12.

He finished his fourth season in the league with 96 combined tackles (80 solo), ten pass deflections, two interceptions, a touchdown, and was credited with half a sack in 16 games and 16 starts.

[28] He received serious interest from multiple teams, including the Cincinnati Bengals, Tampa Bay Buccaneers, Denver Broncos, Carolina Panthers, Minnesota Vikings, Dallas Cowboys, and Houston Texans.

[38] On November 18, 2012, Weddle recorded six combined tackles, deflected a pass, and returned an interception for a touchdown in a 30–23 loss at the Denver Broncos in Week 11.

[40] On December 31, 2012, the San Diego Chargers fired general manager A. J. Smith and head coach Norv Turner after finishing the season with a disappointing 9–7 record.

He read a prepared statement and said, Contrary to what has recently been said by upper management, there has never been any financial numbers discussed and the Chargers have never put an offer on the table for us to consider.

I am extremely excited about re-joining my teammates today and getting back to the practice field and working to bring a Super Bowl trophy to San Diego.

[56][57] After the game, Weddle and several other Chargers players returned to the field to sign autographs for the fans, as they were unsure if it would be the team's final time playing in San Diego.

Weddle's agent, David Canter, said he planned to file a grievance with the NFL Players Association and said that he felt disrespected by the way things were handled.

[70] On December 3, 2017, Weddle made three combined tackles, a pass deflection, recorded a strip/sack, and returned an interception for a touchdown during a 44–20 victory against the Detroit Lions in Week 13.

[74] He completed the season with 63 combined tackles (49 solo), eight passes defensed, six interceptions, a sack, forced fumble, and touchdown in 16 games and 16 starts.

[87][88] The Rams could only offer Weddle a contract that was prorated by each playoff game played and worth up to a total of $225,000 if the team won the Super Bowl.

This was due to an NFL collective bargaining agreement rule that limited the earnings of a player that joined a team after the regular season, as was Weddle's case.

On his first day back, he met with secondary coach Ejiro Evero, who originally had the idea of reaching out to Weddle after the team lost their starting safeties.

[89] During the Wild Card Round against the Arizona Cardinals, Weddle came off the bench and played nine defensive snaps before suffering a minor hamstring injury, but remained in the game.

In the Divisional Round against the defending Super Bowl champions Tampa Bay Buccaneers, Weddle again came off the bench, but would have an increased load, playing 61 defensive snaps in a 30–27 victory.

The next week, in the NFC Championship against the San Francisco 49ers, Weddle would start, play in every defensive snap and lead the team with nine tackles in a 20–17 win.

[89] Weddle would start again in Super Bowl LVI against the Cincinnati Bengals, and would wear the communication device that designated him as the play caller on defense.

Weddle ended up playing all 61 defensive snaps in the game and recorded five tackles, helping lead the Rams to a 23–20 victory and finally earning him a Super Bowl championship.

[92] He sarcastically thanked Chargers general manager Tom Telesco for his acrimonious end with the franchise, saying that their failure to re-sign him was key to "showing me the light, and giving me that motivation and that fire".

[91] When reflecting on his decision to come out of retirement and ending his career after winning the Super Bowl, Weddle said "certain things had to happen for me to be in this moment, and to finish it off the way we did is just something you hear out of a book, or a story — a fiction fairy tale you only wish that your name would be a part of it.