Marshall made his major league debut against the St. Louis Cardinals on April 9, 2006, recording a no-decision. In that game he yielded a two-run homer to Scott Rolen in the first inning before settling down to pitch solidly for 4+ innings. The Cubs trailed 4-3 in the late innings, but rallied to win on a Michael Barrett grand slam in the eighth inning. He earned his first major league win on April 14, 2006, against the Pittsburgh Pirates. Marshall indicated his pleasure with the start. He stayed in the starting rotation for the first half of the year before suffering a strained left side muscle. Marshall left the rotation after a crushing loss on July 16 in which the Cubs gave up two grand slams in one inning, blowing a 5-2 lead in the 6th inning against the New York Mets. In 19 starts, Sean posted a 5-8 record with a 4.98 ERA. On September 2, Marshall returned to the Cubs' rotation, but posted a loss against the San Francisco Giants. During the game, he gave up career home run #728 to Barry Bonds in Chicago. In his remaining four starts, Marshall struggled, and completed six innings only once.