The Division III Beavers beat Occidental 46-45 on Tuesday night.
"I hope that everyone who has participated in Caltech men's basketball is able to celebrate a little bit tonight," Caltech coach Oliver Eslinger said. "We still have goals and aspirations that we want to accomplish as a program, and this win is another step towards meeting these objectives."
The game-clinching point came when Caltech player Ryan Elmquist hit the first of two free throws with three seconds left, then a desperation shot by Occidental missed the mark.
It's Caltech's first conference win since 1985.
Caltech is a famed private research university with a heavy emphasis on science and engineering. The school has just 950 undergraduates and doesn't give out athletic scholarships, but 31 alumni and faculty have won the Nobel Prize.
The Associated Press contributed to this story.