Sisco was the Chicago Cubs second-round pick in the 2001 Major League Baseball draft. He was selected to the Northwest League all-star team and short season A All-Star team as well as being named the short season player of the year, in 2002 with the Boise Hawks, when he was 7–2 with a 2.43 ERA in 14 starts.
Sisco was the second pick in the 2004 Rule 5 draft, taken by the Kansas City Royals from the Cubs organization. The Royals converted him to a relief pitcher. He made his Major League debut on April 4, 2005 against the Detroit Tigers, allowing two runs in 2 innings. Under the terms of Rule 5, Sisco remained on the Royals major league roster for the entire 2005 season so that he would not have to be offered back to the Cubs for $50,000. Sisco posted a 3.11 ERA in his rookie season for the Royals, but after struggling during the 2006 season, the Royals sent Sisco to Triple-A Omaha. They recalled him to Kansas City on August 8. His ERA rose to 7.10 in 2006.
On December 16, 2006, Sisco was traded to the Chicago White Sox for Ross Gload. He appeared in 19 games for the White Sox, with an 8.36 ERA in 2007 and also made 23 appearances (15 starts) for the AAA Charlotte Knights.
Following Tommy John surgery, Sisco was signed by the Oakland Athletics to a $550,000 minor-league contract in March 2009. Due to his lengthy recovery from the injury, he did not play in a game for the Athletics.
On March 6, 2010, Sisco signed a minor league contract with the San Francisco Giants. He appeared in 48 games with the AA Richmond Flying Squirrels, where he was 4–4 with a 4.32 ERA.
Sisco signed a minor league contract with an invitation to 2011 spring training with the New York Yankees. However, he did not make the team out of spring training. On May 27, Sisco was released after he had a 2–0 record and a 1.88 ERA in 16 games with the Scranton/Wilkes-Barre Yankees of the International League. He finished the season with the Piratas de Campeche in the Mexican Baseball League, where he was 1–2 with an 8.27 ERA with 10 appearances.
The Los Angeles Dodgers signed Sisco to a minor league contract on February 9, 2012.
In 2013, Sisco played the first half-season for the EDA Rhinos, a team in Taiwan's Chinese Professional Baseball League, where he is primarily used as a starting pitcher. Despite only playing for the first half, Sisco led the league in ERA with 2.70 in 133 and 1/3 innings.
In 2014, Sisco returned to the Rhinos with a one-year contract.