Striding confidently on the same Hayward Field track where she won the 400m hurdles at worlds in record time last year, McLaughlin wrested the early lead in her new event and never gave her opponents much of a shot in a clinical run.
Britton Wilson finished second in 49.79 and Talitha Diggs was third in 49.93.
McLaughlin will now have the opportunity to compete in both the hurdles and the flat event at the world championships in Budapest, Hungary, which kick off on August 19th, if she chooses.
"The greats always push themselves and I want to be one of them so I have to push myself and get out of my comfort zone, so I'm just happy to be here," a breathless McLaughlin said in a trackside televised interview, after breaking the tape just shy of the US record.
Olympic silver medallist Nia Ali banished the memory of her doomed 2022 world championships run to win her first national title the 100m hurdles in 12.37, with Olympic silver medallist Kendra Harrison taking second in 12.42.
Ali's world title defence ended in heartbreak last year when she hit a hurdle and crashed out of the heats. But she showed no lack of confidence on Saturday as she exploded out of the blocks and took the outright lead after the second hurdle.
Masai Russell grabbed the third ticket to Budapest by just two thousandths of a second in 12.46.
Nikki Hiltz came out on top in the women's 1500m in 4:03.10 while the 800m Olympic and world champion Athing Mu crossed the finish in second with 4:03.44. Yared Nuguse won the men's side in 3:34.90.
Christian Coleman showed no signs of fatigue after finishing second in Friday night's 100m final, advancing in the men's 200m heats in 20.06, six hundredths of a second behind the fastest finisher Robert Gregory.
Fred Kerley, who has an automatic spot at worlds in the 100m as the reigning title-holder in the shorter distance, also moved on to Sunday's 200m semi-final in 20.23.
Twice world champion Grant Holloway easily advanced from the opening 110m hurdles heats in 13.07 while Devon Allen, a wide receiver on the Philadelphia Eagles practice squad, moved on by the skin of his teeth in 13.51.
World leader Maggie Ewen won the women's shot put on her last throw with a 19.92-metre effort, while the reigning world champion Chase Ealey was unable to improve upon 18.62 and finished fourth.
Olympic and world silver medal pole vaulter Chris Nilsen booked his trip to Budapest with a 5.91-metre leap, as twice world champion Sam Kendricks finished just shy of the podium with 5.81 metres.
Rudy Winkler came out on top in the men's hammer throw with 79.04 metres on his second attempt while Curtis Thompson won the javelin with 80.92 metres, his best of the season.
The top three finishers across all events in Eugene who meet certain qualifying standards, as well as reigning global title-holders, will advance to the world championships.
The US championships wrap up on Sunday.
