Lia Thomas became the first known transgender athlete to win the highest US national college title with victory in the women's 500-yard freestyle.
Thomas, who swims for the University of Pennsylvania, secured the title in four minutes 33.24 seconds in Atlanta.
Virginia's Emma Weyant, who won 400m individual medley silver at the Tokyo Olympics, finished 1.75secs behind in second while Erica Sullivan was third.
"It means the world to be here," Thomas told ESPN.
Sullivan, who finished third, was also a silver medallist at the Tokyo Games in the 1500m freestyle.
Thomas will also compete in the 200- and 100-yard events later in the week.
She swam for the Pennsylvanian men's team for three seasons before starting hormone replacement therapy in spring 2019.
The National Collegiate Athletic Association Division I is the highest level of intercollegiate athletics in America.
US swimming updated its policy in February to allow transgender athletes to swim in elite events, alongside criteria that aims to reduce any unfair advantage.
There were some protestors outside the venue and in the stands at Georgia Tech on Friday.
Some swimmers have criticised the decision to allow Thomas to compete, with one Virginia Tech student telling a reporter it was "heartbreaking" to see how upset a fellow competitor was by the decision.
"I try to ignore it as much as I can," Thomas said.
"I try to focus on my swimming, what I need to do to get ready for my races, and just try to block out everything else."