Andy McDonald left his hometown of Strathroy, Ontario to play collegiate hockey with Colgate University in Hamilton, New York in the fall of 1996. During his four seasons with Colgate, McDonald established himself as a high-scoring centre and in 1999-2000, led the ECAC in goals (25), assists (33) and points (58), while being named to the ECAC First All-Star Team, ECAC Player of the Year, NCAA First All-Star Team and was named a finalist for the Hobey Baker Award.
Undrafted, McDonald was signed as a free agent with the Mighty Ducks of Anaheim in April 2000. In 2000-01, McDonald played 16 games with the NHL's Mighty Ducks, while spending the remainder of the season with Cincinnati of the AHL. The next season, McDonald again split the season between Anaheim and the AHL before earning a full-time roster spot with the club in 2002-03.
McDonald became a regular in the Mighty Ducks' line-up throughout the 2003-04 season and would spend his following season in Germany due to the NHL lockout. He returned in 2005-06 and tallied a career high 34 goals, 51 assists for 85 points with the Ducks. He became only the third player in franchise history to surpass the 80-point plateau. In 2006-07 McDonald recorded 78 points in his seventh NHL season, and was selected to comepte in the 2007 NHL All-Star game in Dallas, Texas, where the Strathroy, Ontario native won the competition for fastest skater. That year, McDonald and the Ducks captured the Stanley Cup by defeating the Ottawa Senators in five games.
On December 14, 2007, in order for the Anaheim Ducks to free up salary cap space for Scott Neidermayer, McDonald was traded to the St. Louis Blues for Doug Weight.
On the international stage, McDonald represented his homeland at the 2002 World Championships.