He spent his first professional campaign split between the rookie-level Arizona League Mariners and the Low-A Everett AquaSox.

[3] On February 9, 2008, Tillman, along with Adam Jones, George Sherrill, Kam Mickolio, and Tony Butler, were traded to the Baltimore Orioles for Érik Bédard.

[5] On July 29, 2009, the Orioles selected Tillman's contract from Norfolk, and he would make his major league debut against the Kansas City Royals.

On April 28, 2010, Tillman threw a no-hitter at the Gwinnett Braves as the Triple-A Norfolk Tides won the game 6–0.

On April 2, 2011, Tillman carried a no-hitter through six innings against the Tampa Bay Rays in the Orioles second game of the season.

Tillman made his return to the Orioles on July 4, 2012, allowing only 2 hits over 81⁄3 innings against the Mariners and recording his first major league win of the season.

Although he did not get the call to pitch, Tillman was selected to his first All Star Game, by American League manager Jim Leyland, after Justin Verlander decided not to go.

On August 29, Tillman became the first Oriole pitcher since Erik Bedard in 2006 to record 15 victories in a single season, winning against the Boston Red Sox, pitching 7 innings, allowing two runs, no walks and striking out 8.

Tillman made his first career postseason start during Game 1 of the American League Division Series, against the Detroit Tigers.

However, he struck out the final five batters he faced, and the Orioles went on to win in the bottom of the ninth 3–2, giving them their sixth consecutive Opening Day victory under manager Buck Showalter.

On June 8, Tillman pitched his best game of the year, going 71⁄3 shutout innings, walking no batters, and tied a career-high with nine strikeouts.

On July 21, after tossing seven innings of one-run ball to snap a four-game losing streak for the O's, Tillman recorded his 14th win of the season.

On October 3, Tillman was named the starting pitcher for the Orioles Wild Card game against the Toronto Blue Jays.

Tillman left the game with runners on the corners, and teammate Mychal Givens came in and induced a double play.

The win was Tillman's 73rd career victory, tying him with Sidney Ponson and Lefty Stewart for 20th in franchise history.

[15] After struggling through his first four starts, Tillman pitched seven one-hit, shutout innings against the Tigers to earn his first win in 27 appearances dating back to May 2017.

[17] He made four appearances for the Triple-A Round Rock Express to finish the year, struggling to a 9.00 ERA with 5 strikeouts in 9 innings pitched.

[18] Tillman did not play in a game in 2019, taking the season off after having surgery to clean up the labrum in his right shoulder in June.

[19] On December 27, 2019, it was announced that Tillman was attempting a comeback and was planning to throw for teams in Spring Training for the 2020 season.

He had been working with his former pitching coach in Baltimore, Dave Wallace at Cressey Sports Performance since February.