He played college football for the Oklahoma Sooners, where he was recognized as an All-American, and was selected by the Washington Redskins fourth overall in the 2010 NFL draft.

Williams is considered one of the greatest offensive tackles of all time, having made eleven Pro Bowls and four All-Pro teams.

In 2019, Williams held out the entire year with the Redskins due to contractual and personal grievances regarding a cancerous growth on his head downplayed by the team but later determined by private doctors to be life-threatening.

Longview entered the 2005 UIL playoffs on a 10–0 season record, but lost 14–13 to Nick Florence's South Garland.

In his sophomore year, Williams saw action in all 14 games and had six starts at right tackle, sharing time with Branndon Braxton.

He was part of a dominant 2008 Sooners offensive line that included Duke Robinson, Phil Loadholt, and allowed only 11 sacks all season, the third-lowest total of any team in the country.

Oklahoma attempted 476, and—featuring quarterback Sam Bradford and running back DeMarco Murray—became the highest-scoring team in the modern era (702 points).

[8] Despite missing the regular season finale due to injury, Williams led Oklahoma with 102 knockdown blocks and 885 plays, and was named an All-American by the American Football Coaches Association.

[9] Williams was considered one of the best offensive tackles available in the 2010 NFL draft,[10][11][12][13][14] and drew comparisons to Jammal Brown (who, coincidentally, would also join the Redskins that same offseason via trade).

Williams started 10 games in 2017 while dealing with a knee injury for most of the season, and was placed on injured reserve on December 22, 2017.

[37][38] In April 2019, it was reported that Williams had a surgical procedure done to remove a growth from his head that was diagnosed as dermatofibrosarcoma protuberans (DFSP), a type of cancer.

[43][44] However, Williams failed to pass a physical exam, as he experienced discomfort with his helmet due to his scalp having postsurgical soreness, which resulted in the Redskins placing him on the non-football injury list.

[48] The trade reunited Williams with San Francisco 49ers' head coach Kyle Shanahan, who previously held the offensive coordinator position with the Washington Redskins.

[52] On January 1, 2021, Williams was placed on injured reserve after suffering an elbow injury against the Arizona Cardinals in the previous week.

[56] On March 23, 2021, Williams signed a six-year, $138.06 million contract extension with the 49ers, making him the highest-paid offensive lineman in the NFL.

[65] On January 29, 2023, Williams was ejected during the NFC Championship for violently slamming Philadelphia Eagles safety K'Von Wallace to the ground after a scuffle between both teams.

On December 23, after the 49ers were eliminated from the playoffs with their Week 16 loss to the Miami Dolphins, Shanahan announced that Williams would not return for the final two games of the season.

[76][77] Williams is the subject of a documentary called Silverback, which debuted in December 2021 and covered his comeback from a life-threatening sarcoma on his scalp.