McGwire hit a solo home run to left-centre field off Jason Christianson, the Pittsburgh Pirates pitcher, with one out in the ninth innings. Pittsburgh won 8-6 in the opening game of a double-header.
McGwire, who broke Roger Maris's 37-year-old record of 61 a week ago, hit the pitch 385 feet.
"People cheer `come on Mark, we want you to hit one.' Boom, he hits it," said Tony La Russa, the Cardinals manager. "How he does it, I have no idea. He is just remarkable."