The 24-year-old came up through the ranks of the German youth system but opted to play for Ghana in the 2010 World Cup, helping his team reach the quarterfinals of the competition.
Boateng was a member of Milan's Serie A title team last season and cited the physical demands of playing for both club and country as his main reason for stepping away from the Black Stars.
A statement read: "The Ghana Football Association has received a letter from player Kevin Prince-Boateng on his decision to resign from the senior national team, the Black Stars.
"According to Kevin, the physical demands of playing for both club and country at high levels are taking a toll on his health."
Boateng earned nine caps for Ghana and scored one goal in his brief international career.