At the time of his retirement, Williams ranked among the top players in Bills history in tackles and sacks and made six Pro Bowls.

He was a member of the Baton Rouge Advocate Super Dozen and the New Orleans Times-Picayune Blue Chip Top 15 for Louisiana.

[10] Head coach Dick Jauron named Williams the backup defensive tackle to start the season, behind Larry Tripplett and Tim Anderson.

He made his professional regular season debut in the Buffalo Bills' season-opener at the New England Patriots and recorded six combined tackles in their 19–17 loss.

[12] On October 16, 2006, Williams earned his first career start after surpassing Tim Anderson on the depth chart and made five combined tackles during a 20–17 loss at the Detroit Lions.

[16][14] Williams entered training camp slated as a starting defensive tackle, but saw minor competition from John McCargo and Tim Anderson.

[18] On October 28, 2007, Williams recorded four combined tackles and made his first career sack on quarterback Chad Pennington during a 13–3 victory at the New York Jets in Week 8.

On December 28, 2008, Williams recorded a season-high six solo tackles and sacked quarterback Matt Cassel in the Bills' 13–0 loss to the New England Patriots in Week 17.

[16] Head coach Dick Jauron retained the entire starting defensive line from the previous season, including Williams, Marcus Stroud, Chris Kelsay, and Aaron Schobel.

On October 11, 2009, Williams collected a season-high ten combined tackles (seven solo) and sacked quarterback Derek Anderson in a 6–3 loss to the Cleveland Browns in Week 5.

He entered training camp slated as the starting nose tackle, but saw minor competition from rookie Torell Troup.

[30] On November 28, 2010, he collected a season-high ten combined tackles (eight solo) and sacked quarterback Ben Roethlisberger twice in the Bills' 19–16 loss to the Pittsburgh Steelers in Week 12.

[16] On January 6, 2011, it was announced that Williams selected to play in the 2011 Pro Bowl as a replacement for Richard Seymour who was unable to participate due to a hamstring injury.

[35] Williams remained the starting nose tackle in 2011, alongside defensive ends Dwan Edwards and Marcell Dareus.

[16] On January 2, 2012, head coach Chan Gailey announced the decision to fire defensive coordinator George Edwards.

[43] In Week 4, Williams recorded a season-high five combined tackles, a pass deflection, and was credited with had a sack during a 52–28 loss to the New England Patriots.

In Week 11, Williams recorded three solo tackles and made a season-high two sacks on quarterback Geno Smith during a 37–14 victory against the New York Jets.

Schwartz also used a wide 9 technique with aggressive play calling and used minimal blitzing by only pass rushing with the defensive line.

He started in the Buffalo Bills' season-opener at the Chicago Bears and recorded a tackle, a pass deflection, and made his first career interception in their 23–20 overtime victory.

Williams intercepted a pass by quarterback Jay Cutler, that was intended for tight end Martellus Bennett, and returned it two-yards before being horse collar tackled by wide receiver Brandon Marshall.

On October 18, 2015, Williams recorded one tackle before sustaining a knee injury and was carted off the field in the second quarter of a 34–21 loss to the Cincinnati Bengals in Week 6.

[16] Throughout training camp, Williams competed for the role as the starting nose tackle against Marcell Dareus, Corbin Bryant, and Adolphus Washington.

Head coach Rex Ryan named Williams the starting nose tackle to begin the regular season.

Williams was also named a first-team defensive tackle, alongside Corbin Bryant, after Marcell Dareus was suspended for the first four games for violating the league's substance abuse policy.

[16] On January 20, 2017, it was announced that Williams was added to the 2017 Pro Bowl as a late replacement for Ndamukong Suh, who was unable to play due to injury.

[65] After the firing of Rex Ryan the previous season, new head coach Sean McDermott hired Leslie Frazier as the Buffalo Bills' new defensive coordinator.

[72] On January 7, 2018, Williams started in his first career playoff game and made one solo tackle in the Bills' 10–3 loss at the Jacksonville Jaguars in the AFC Wild Card Round.

In what ended up being the final play of his NFL career, he lined up as an extra fullback on offense and caught a pass, advancing the ball nine yards.

[84] On March 11, 2020, it was announced that Williams accepted the Defensive Coordinator coaching position at Ruston High School, his alma mater.