He made his top-flight debut with the Pittsburgh Pirates on Wednesday evening against the Chicago Cubs.
Ngoepe, 27, grew up in Randburg, near Johannesburg, where his mother worked at the local baseball club.
He signed for Pittsburgh in 2008 but has been playing in the lower leagues since then, until he was recalled on Wednesday.
"You could totally see the emotion on his face, it was really a wonderful moment to be part of," MLB.com's Adam Berry told the BBC's Newsday programme.
"It's a dream come true for me because it's been my dream since I was a 10-year-old boy, but it also means so much to the people of South Africa and baseball in Africa," Ngoepe said before the game, the New York Times reports.
This is his ninth year playing baseball in the US and he started at the lowest level, in a rookie league, before making his way up to the MLB.
Talking after the game Ngoepe, said that he almost burst into tears when he took to the field.
"I was holding it back. I was like, 'You know what, you're in the big leagues. You've got to be a big guy.'â€¦ We live for this kind of moment," MLB.com quotes him as saying.
Ngoepe started playing seriously at the age of 12 and had access to the game because his mother worked at the Randburg Mets baseball club.
"The clubhouse was my house and the field was my backyard," he told South African news channel EWN.
His younger brother, Victor, has also been signed to the Pirates and is touted as the next African to get into the MLB.
Ngoepe got to first base after appearing as a batter for the first time in the game's fourth inning. He also batted in the sixth and eighth innings.
The Pirates beat the Chicago Cubs 6-5.
South Africa's Gift Ngoepe has become the first Africa-born player to feature in a Major League Baseball (MLB) game.