Scott Spiezio's journey in Major League Baseball began when he was drafted by the Oakland Athletics in the sixth round of the 1993 MLB Draft. He made his debut with the Athletics on September 14, 1996, stepping into the league as a promising infielder. Spiezio's early years with Oakland saw him primarily playing as a first baseman and second baseman, where he demonstrated solid defensive skills and a reliable bat.

In 2000, Spiezio's career took a new turn when he was traded to the Anaheim Angels. It was with the Angels that he experienced some of the most memorable moments of his career. During the 2002 season, Spiezio played a crucial role in the Angels' lineup, contributing significantly to their offensive efforts. His performance in the postseason was particularly noteworthy. In the World Series against the San Francisco Giants, Spiezio hit a pivotal three-run home run in Game 6, which helped the Angels overcome a five-run deficit. This moment is often remembered as one of the highlights of the series, as the Angels went on to win their first World Series title in franchise history.

Following his success with the Angels, Spiezio signed with the Seattle Mariners in 2004. His time in Seattle, however, was marred by injuries and inconsistency at the plate. Despite these challenges, he continued to be a versatile player, capable of filling multiple roles on the field. After two seasons with the Mariners, Spiezio was released in 2005.

In 2006, Spiezio found a new opportunity with the St. Louis Cardinals. He enjoyed a resurgence in his career, providing valuable depth to the Cardinals' roster. His contributions during the 2006 season helped the Cardinals secure a spot in the postseason. Spiezio's performance in the playoffs was instrumental in the Cardinals' journey to winning the World Series that year, marking his second championship win.

Spiezio's tenure with the Cardinals lasted until 2007, after which his career faced challenges both on and off the field. Despite these difficulties, his time in Major League Baseball is remembered for his clutch performances in critical games and his ability to adapt to different roles on the field. Throughout his career, Spiezio played in over 1,200 games, amassing more than 800 hits and over 100 home runs.