Mebane was selected by the Seattle Seahawks in the third round, 85th overall of the 2007 NFL draft, and on July 24, he signed a four-year contract.

With the departure of Rocky Bernard, Mebane was expected to make a big impact for the Seahawks in 2009 in which he started 15 games and recorded 49 tackles and 1.5 sacks.

[5] Mebane has been a constant in the middle and helped the 2013–2014 Seahawks defense reach dominant heights, as they had one of the best seasons in NFL history.

[6] Mebane, along with defensive linemen Red Bryant, center Max Unger and punter Jon Ryan, were the only four holdovers on the Super Bowl winning team roster from pre-Carroll/Schneider era.

Fellow Seahawks teammate Richard Sherman was quoted as saying of Mebane: "He's an incredibly technical player in his movements and everything he does.