Mebane was selected by the Seattle Seahawks in the 3rd round, 85th overall of the 2007 NFL Draft and on July 24 he signed a four-year contract. In his rookie season he played all 16 games and recorded 29 tackles including 2 sacks. 2008 was a promising year for Mebane as he again played all 16 games and recorded 39 tackles, 5.5 sacks, and 2 forced fumbles. 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. For the 2010 season Mebane started the first four games but suffered a calf injury and was forced to sit out the next 4 games. In the first 4 games he had 8 tackles and 1 sack. Mebane has been a constant in the middle and helped the 2013-2014 Seahawks defense reach dominant heights, as they went down as one of the best in history. The Seahawks would go on to win Super Bowl XLVIII against the Denver Broncos. On February 2, 2014, the Seahawks won their first Super Bowl Championship, defeating Denver 43-8. Brandon Mebane, along with defensive linemen Red Bryant, center Max Unger and punter Jon Ryan, were the only 4 holdovers on this Super Bowl team 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. He's rarely out of position and he's rarely out of the play. You rarely see a defensive tackle running making tackles on the sideline, or [making] tackles on screen plays. He does all that. But once again, he's overlooked because I guess he's not a big sack-total guy. He's just a guy that does his job incredibly well week in and week out."