In 2002, Mario Williams was the first overall pick in the draft, and he played his first four seasons in football with the team that drafted him, the Houston Texans.  Mario Williams signed a massive free-agent contract with the Buffalo Bills in March 2012. Landing in Western New York as the cornerstone of the defense, Williams immediately validated the record-breaking deal by establishing himself as one of the most dominant edge rushers in franchise history.

Williams was a rare physical specimen combining elite size, functional strength, and explosive initial quickness. Operating primarily as a 4-3 defensive end, his primary trait on tape was converting speed into power; he routinely overwhelmed offensive tackles with a punishing bull rush, using his long reach to disengage and collapse backfields toward the quarterback.

Williams made an immediate impact in his inaugural season in Western New York (2012), leading the Bills with 10.5 sacks despite competing through a wrist injury. In 2013, he received his third career Pro Bowl selection and Second-Team All-Pro honors after accumulating 13.0 sacks, including a franchise single-game record-tying 4.5-sack performance against the Carolina Panthers.

His remarkable peak came in 2014 when he played a vital role in Buffalo’s well-known "Cold Front" defensive line, teaming up with Marcell Dareus, Kyle Williams, and Jerry Hughes. Williams achieved a career-best 14.5 sacks, 19 tackles for loss, 18 Approximate Value (AV), and two forced fumbles. His outstanding performance earned him First-Team All-Pro honors and his fourth Pro Bowl selection, contributing to Buffalo leading the NFL in total sacks with 54.

Following a coaching change and scheme shift in 2015 (5.0 sacks), Williams was released and signed with division rival Miami for his final NFL season in 2016. Over his four years with the Bills (2012–2015), Williams started all 63 games, recording 43.0 sacks, 52 tackles for loss, 193 tackles, and seven forced fumbles.