Back in good health in 2010, Pineda was 8–1 with a 2.22 ERA for the West Tenn Diamond Jaxx of the Class-AA Southern League with 78 strikeouts and 17 walks in 77 IP and 3–3 with a 4.76 ERA for the Tacoma Rainiers of the Class-AAA Pacific Coast League with 76 strikeouts and 17 walks in IP. The Mariners front office ended his season when he reached 140 IP as a precaution against injury. The Mariners again named Pineda their Minor League Pitcher of the Year in 2010, and he was a finalist for the "USA Today" Minor League Player of the Year. "Baseball America" rated Pineda as the second best prospect in the Mariners' system before the 2011 season. "Baseball America" also rated him the sixteenth best prospect in all of baseball. Pineda made the Mariners' starting rotation out of spring training 2011 as the number five starter, the third youngest player on a 2011 American League opening day roster after Chris Sale and Tim Collins. He made his MLB debut on April 5, giving up three runs in six innings in a loss. Pineda pitched innings, allowed two runs, struck out seven batters, and earned his first MLB win on April 12, 2011. Pineda struck out a career high nine batters against the Detroit Tigers on April 28, including the first four batters he faced. He ended his first month in the majors with a 4–1 record and a 2.01 ERA. He was named American League Rookie of the Month for April 2011, pitching at least six innings in his first five starts, giving up only 22 hits and 12 walks over innings, while striking out 30 opposing batters. Pineda was selected to the All-Star Game on July 10 as a replacement for Justin Verlander, who was ineligible to pitch in the All-Star Game due to having pitched the day before the All-Star break. He was 8–6 at that point, but with a 3.03 ERA and 113 strikeouts in 113 innings, against only 36 walks. In the All-Star Game, Pineda pitched one perfect inning, striking out Scott Rolen and Rickie Weeks. Pineda finished the 2011 season with a 9–10 record and a 3.74 ERA. He recorded no wins in his final seven starts over the last two months of the year, and the Mariners cut back on his work load as a precaution against an arm injury. In 28 starts, he struck out 173 hitters while walking just 55 over 171 innings.