In Major League Baseball (MLB), he played for the Pittsburgh Pirates, Cleveland Indians, Toronto Blue Jays, and Kansas City Royals.

During his freshman season, an injury to staff ace Justin Wechsler allowed Bullington to become the Friday night starter.

Bullington went 9–3 during the regular season with a conference-best 3.01 ERA, and was honored as a unanimous choice for MAC's Pitcher of the Year, becoming the first Cardinal to win the award.

[6] Bullington started the Cardinals opening game of the conference tournament against Miami University, but was removed in the first inning after being struck in the face by a line drive off the bat of Brady Nori.

In his third start of the season, he tossed 8 strong innings in a winning effort over the defending National Champion and 17th ranked Miami Hurricanes.

[10][11] On May 3, Bullington struck out a career-high 15 batters against Eastern Michigan, surpassing Bob Owchinko for the most career strikeouts in MAC history.

[13] Bullington and the Cardinals were seeded fourth in the conference tournament and slated to face Kent State in their opening game.

In an effort to avoid a repeat of the first game, Coach Rich Maloney chose to bring Bullington out of the bullpen in relief.

The Pirates assigned him to their Class–A affiliate, the Hickory Crawdads, and he appeared in eight games (seven starts) for them, going 5–1 with a 1.39 ERA over 451⁄3 innings before being promoted to the Advanced-A Lynchburg Hillcats.

He was assigned to the Pirates' Double–A affiliate, the Altoona Curve, and in his first 17 starts, he went 6–5 with a 3.89 ERA, earning him a spot in the Eastern League All-Star Game.

[28] On September 16, the Pirates called Bullington up to the major leagues, along with José Bautista, Matt Capps, Tom Gorzelanny, and Ronny Paulino.

[29] On September 18, he made his major league debut against the Cincinnati Reds, relieving starting pitcher Óliver Pérez in the third inning with two outs.

On June 10, Bullington left a game after pitching only one inning due to shoulder discomfort, and was placed on the 15-day disabled list.

When asked about the move, Bullington said, "I really appreciate everything the Pirates have done for me, but I feel like a fresh start with another organization wouldn't be such a bad thing at this point.

[47] After Spring training, when asked about his time in Buffalo, Bullington said, "Pitching coach Scott Radinsky had me drop my arm slot, and I got back to where I was in college, feeling more comfortable and getting some more action on the ball.

[52] Bullington reported to camp with the Kansas City Royals for Spring training, where they moved him back into his original role as a starter.

He made two relief appearances before being moved back into the starting rotation in late April after Bruce Chen was promoted to the majors.

[68] Bullington was moved back to the bullpen as a long reliever for September when two regular starters returned from the disabled list.

On November 24, the Royals placed Bullington on unconditional release waivers, freeing him to sign with the Hiroshima Toyo Carp of Japan's Central League.

[70][71][72] Years later, Bullington would say of his only major league win: "I remember they told me I was done after eight, and just going into the tunnel for a second before I came back out to watch the ninth.

[73] When asked why he decided to come to Japan, he said "The last few years I had to start the season from the minors and wait for a players at the MLB level to have a bad streak or get injured.

He pitched two innings in Game 3 of the series, allowing two hits, one being a solo home run to Takahiro Okada, and struck out one.

On December 11, the Carp announced that they had re-signed Bullington to a two-year deal worth approximately $1.25 million plus incentives per year.

On March 22, the Carp announced Bullington would get the opening day start to give Maeda extra rest after pitching in the World Baseball Classic.

[82][83] On April 29, Bullington made news in the United States for throwing behind Hanshin Tigers batter Ryota Arai.

He continued his hot pitching through September, defeating both the Yomiuri Giants and the Hanshin Tigers in his next two starts as the Carp chased a playoff spot.

[86] On September 25, Bullington got the start against the Chunichi Dragons as the Carp looked to clinch a playoff spot for the first time in 23 years.

[92] Despite concern from Manager Kenjiro Nomura over poor performance in the preseason,[93] Bullington got his fourth season with the Carp off to a great start.

On August 20, Hiroshima announced that Bullington would be removed from the roster for 10 days of rest after giving up seven earned runs in three innings against the Yokohama DeNA BayStars.

[95] Bullington was diagnosed the next day with neuritis in his ulnar nerve, also known as inflammation of the funny bone, and was shut down for the rest of the season.