Epenesa was the top pick for One Bills Drive, as the team had sent its first-round pick that year to the Minnesota Vikings as part of the trade that sent wide receiver Stefon Diggs to Western New York. Selected 54th overall by Buffalo, Epenesa spent six seasons with the Bills — first as part of his four-year rookie contract, then returning via a two-year, $12 million contract extension ahead of the 2024 NFL season.
During his time with Buffalo, Epenesa was an integral part of former head coach Sean McDermott’s rotation-heavy defensive front four. However, he never was able to crack into a featured role with the defense, early in his career being asked to add weight before it was clear that only hindered his abilities.
After slimming back down to a more comfortable playing weight, Epenesa began to blossom as a pass disruptor at the line of scrimmage. His knack for perfectly timing jumps in all directions meant bad things for opposing quarterbacks, and Epenesa would end up with the football often enough for it to become a healthy habit. Yet, as a sack artist, Epenesa left a lot to be desired up front — never totaling more than 6.5 sacks in any single season with the Bills.