Lowry was first drafted out of Nordhoff high school, in Ojai California, by the Texas Rangers in the nineteenth round of the 1999 MLB Draft, but instead opted to attend Pepperdine University. At Pepperdine, Lowry went 14-2 with a 1.71 ERA as a junior.

Following a September call-up in 2003, Lowry enjoyed a very successful partial rookie year for the Giants in 2004, going 6-0, and finishing with a 3.82 ERA in fourteen starts. He was named the National League's Player of the Week for the week of August 9. With an early victory to start off the 2005 season, Lowry began his career with a 7-0 record, the longest winning streak for any pitcher in San Francisco Giants history (and the second longest in Giants franchise history, behind Hooks Wiltse's 12-0 start in 1904).

In eighteen starts before the 2005 All-Star break, Lowry posted an ERA of 5.07. He had an 8-4 record and a 2.43 ERA after the break. Lowry's best month came in August, when he went 5-0 with a 0.69 ERA, which earned him Pitcher of the Month honors. He finished the season with a 13-13 record, 3.78 ERA, and 172 strikeouts in 204⅔ innings.

Prior to the 2006 season, the Giants signed Lowry to a four-year deal with an option for a fifth year, valued at $9.25 million. At the time, it was the second largest contract for a pitcher with only one full season of big league service. Lowry received a $1 million signing bonus and $385,000 salary for 2006. The contract guarantees him totals of $1.115 million for 2007, $2.25 million for 2008, and $4.5 million for 2009. The contract includes a 2010 option for $6.25 million that will be activated automatically if a certain number of starts, innings and Cy Young Award vote placement is achieved. The 2010 option also includes another $1.5 million in incentives.

Injuries hampered his performance right from the beginning of the 2006 season. In his first start of 2006, Lowry was removed from the game in the second inning due to an oblique strain, forcing him to miss the first month of the season. Lowry also suffered from an elbow injury in September.

Despite a losing season for the Giants in 2007, and a season cut short by a forearm injury, Lowry managed to win a career high 14 games, the most for any pitcher on the Giants staff. He finished the season with a 14-8 record and a 3.92 ERA.

Lowry was slated as the number three starter for the Giants in 2008, but the forearm injury that shut him down in 2007 kept him out of the 2008 season. After having trouble throwing strikes early on in spring training, Lowry was diagnosed with exertional compartment syndrome and had surgery on his left forearm.

In May 2009 Lowry had rib removal surgery to relieve the continued pain in his shoulder and neck associated with his recent diagnosis of thoracic outlet syndrome. The new diagnosis brings the original diagnosis of exertional compartment syndrome into question along with the necessity of his 2008 surgery.