He started in the Seattle Seahawks' season-opener at the Arizona Cardinals and made four solo tackles, two pass deflections, and intercepted a pass by John Skelton in their 20–16 loss. On October 14, 2012, Sherman made three solo tackles, three pass deflections, and an interception during a 24–23 win against the New England Patriots. After the game, Sherman taunted quarterback Tom Brady and posted a photo of himself yelling at Brady with "U mad bro?" superimposed on it on his Twitter account. He later removed the post. Prior to Week 8 against Detroit, Sherman nicknamed himself Optimus Prime, an action intended to send out the message that he would shut down Detroit's wide receiver, Calvin Johnson, known by his nickname Megatron. He collected a season-high eight combined tackles and held Calvin Johnson to three catches for 46-yards as the Seahawks lost 28–24 at the Detroit Lions. On November 11, 2012, Sherman recorded three combined tackles, three pass deflections, an interception, and made his first career sack during a 28–7 win against the New York Jets. Sherman sacked quarterback Mark Sanchez and forced a fumble that was recovered by teammate Jason Jones in the fourth quarter. On November 25, 2012, it was reported that Sherman and teammate Brandon Browner were both facing four-game suspensions after they were accused of taking Adderall which violated the league's policy against performance-enhancing substances. On December 9, 2012, Sherman recorded two combined tackles, deflected three passes, recovered a fumble, made two interceptions, and returned an interception for his first career touchdown during the Seahawks' 58–0 victory against the Arizona Cardinals. Sherman intercepted a pass by quarterback John Skelton, that was originally intended for wide receiver Larry Fitzgerald, and returned it for a 19-yard touchdown in the second quarter. In Week 16, Sherman made five combined tackles, a season-high four pass deflections, and intercepted a pass by quarterback Colin Kaepernick during a 42–13 victory against the San Francisco 49ers. During the second quarter, Sherman recovered a blocked field goal and returned it for a 90-yard touchdown after teammate Red Bryant blocked a 21-yard field goal attempt by 49ers' kicker David Akers. On December 27, 2012, it was announced that Sherman won his appeal of a four-game suspension for violating the league's performance-enhancing drug policy. Sherman had intentions to sue the league if the suspension was upheld. He started all 16 games in 2012 and made 64 combined tackles (53 solo), a career-high 24 pass deflections, eight interceptions, a touchdown, and a sack. He received an overall grade of 94.3 from Pro Football Focus in 2012.

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