On March 1, 2012, Burnett was injured during batting practice, taking a bunt to the right cheek bone. The orbital fracture required surgery to determine the extent of the injury and duration of recovery, and it was reported that Burnett would be out for at least 2 to 3 months. On April 6, 2012, Burnett began his rehab stint pitching for the Pirates High-A affiliate, the Bradenton Marauders. He made his first start for the Pirates on April 21 against the St. Louis Cardinals.
Burnett became a key component of the Pirates success early in the 2012 season. On June 28, 2012, Burnett became the first Pirates pitcher since Dock Ellis in 1974 to win eight games in a row, moving his record to 9–2 with a 3.31 ERA. He also became a leader in the clubhouse, using his experience to groom the young Pirates pitching staff. Heading into the All-Star break, Burnett had a 10–2 record, 3.68 ERA and the Pirates had won 12 games in a row in which Burnett was the starting pitcher.
On July 31, 2012, Burnett pitched a complete game one-hitter in a win against the Chicago Cubs at Wrigley Field. Burnett came within four outs of pitching his second career no-hitter, but gave up a pinch-hit single with two outs in the eighth inning to rookie Adrian Cardenas, who was called up earlier that day. He improved his record to 13–3, the first time in his career his pitching record was 10 games above .500 and second-best win total of his career. On August 5, 2012 Burnett was named the NL Player of the Week for the first time since 2005. On September 23, 2012, Burnett became the first Pirates' pitcher to win at least 15 games in a single season since Todd Ritchie (15–9) last accomplished the feat in 1999. Burnett would finish his first season in Pittsburgh with a record of 16–10, ERA of 3.51, 202.1 innings pitched with 180 strikeouts and 62 walks (his lowest number of walks since his injury shortened 2006 season), and a WHIP of 1.241.