In his sophomore year, Williams saw action in all 14 games and had six starts at right tackle, sharing time with Branndon Braxton. As a junior in 2008, he started all 14 games, the first at left tackle and the remaining 13 at right tackle, and registered 131 knockdowns. 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. The two teams that finished above them (Air Force and Navy) combined to attempt 231 passes. Oklahoma attempted 476, and—featuring quarterback Sam Bradford and running back DeMarco Murray—became the highest-scoring team in the modern era (702 points).

As the lone holdover from the 2008 offensive line, Williams was listed at No. 2 on Rivals.com′s 2009 preseason offensive tackle power ranking. He was also named to the 2009 Outland Trophy watch list. 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.

Williams was considered one of the best offensive tackles available in the 2010 NFL Draft, and drew comparisons to Jammal Brown (who, coincidentally, would also join the Redskins that same offseason via trade). According to NFL.com’s Gil Brandt, “Williams will be a first-round pick and can be a long-time starter in the NFL”.

Williams was drafted fourth overall by the Washington Redskins and agreed to a six-year, US$60 million contract on July 30, 2010. In 2011, Williams was made an offensive co-captain along with veteran teammate Santana Moss. In Week 14, Williams and teammate Fred Davis were suspended for four games after failing several drug tests.

Williams suffered a bone bruise in his left foot during the first 2012 preseason game against the Buffalo Bills. Despite this injury, he started in the next two preseason games and was fully healed by the season opener against the New Orleans Saints. By the start of the season, his teammates voted for him again to be the offensive team captain. He suffered a right knee injury early in the Redskins’ Week 3 game against the Cincinnati Bengals. After getting an MRI exam the next day, it was reported that Williams had another bone bruise. He was able to play in the next game against the Tampa Bay Buccaneers. Despite playing injured throughout the season, Williams had his best performance in 2012 and was selected for the 2013 Pro Bowl but couldn’t participate in the Pro Bowl due to an injury when a night club fight occurred. After the Redskins’ wild card playoff loss against the Seattle Seahawks on January 6, 2013, Williams struck Seahawks cornerback Richard Sherman in the face. He was fined $7,875 for the incident.

After the Week 11 game of the 2013 season, Williams accused umpire Roy Ellison of swearing at him during the game with his accusation supported by several of his teammates. Ellison was in turn suspended by the NFL for one game. Despite the Redskins having a bad year as a team, Williams was chosen as the team’s only player on the 2014 Pro Bowl team.

During the 2015 offseason, Williams lost nearly 30 pounds, going from a playing weight of roughly 345, to 318. On August 29, 2015, he agreed to a five-year, $66 million contract extension with $43.25 million guaranteed. On November 1, 2016, Williams was suspended four games for violating the NFL’s substance abuse policy. Despite missing the games, Williams was named to his fifth straight Pro Bowl, was first-team All-Pro for the first time. 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. Despite the injury, Williams was named to his sixth straight Pro Bowl.

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. The growth was first noticed in 2013, with him claiming that the Redskins medical staff told him it was not serious at the time. He did not report to the team’s mandatory mini-camp, and reportedly demanded to be released or traded over how the team’s medical staff handled the situation back then. On July 27, 2019, the Redskins placed Williams on the team’s reserve/did not report list. After the Redskins failed to trade him before the trade deadline, he was reinstated on October 30, 2019. 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. In March 2020, he and his agent were granted permission to seek a trade to another team.

On April 25, 2020, Williams was traded to the San Francisco 49ers in exchange for a fifth-round pick in the 2020 NFL Draft and a third-round pick in the 2021 NFL Draft. The trade reunited Williams with San Francisco 49ers’ head coach Kyle Shanahan, who previously held an offensive coordinator position with the Washington Redskins.