The US team of Ryan Murphy, Michael Andrew, Dressel, and Zach Apple touched in 3min 26.78sec to smash the global 3:27.28 mark set at the 2009 world championships.
Britain came second in 3:27.51 and Italy were third in 3:29.17.
The Americans were trailing at 200m after Andrew's breaststroke leg against Britain's Adam Peaty but when Dressel hit the water that all changed.
He clawed back the lead, leaving Apple to finish the job.
Australia win women's Olympic 4x100m medley relay gold
Emma McKeon made Olympic history Sunday in helping Australia upset two-time defending champions the United States to soar to the women's 4x100m relay gold medal Sunday.
Their team of Kaylee McKeown, Chelsea Hodges, McKeon, and Cate Campbell touched in a new Olympic record 3mins 51.60secs ahead of the US in 3:51.73 and Canada in 3:52.60.
It was McKeon's seventh medal in Tokyo, a feat no other female swimmer has ever achieved at a single Olympics.
American Robert Finke wins 1500m to seal Olympic distance double
America's Robert Finke secured the Olympic distance double Sunday by winning the men's 1500m gold medal to go with his 800m title.
The 21-year-old delivered a devastating final 50m to pull clear of a tight field in a race that was neck-and-neck from the off.
Finke touched first in 14mins 39.65secs ahead of Ukrainian Mykhailo Romanchuk (14:40.66) and Germany's Florian Wellbrock (14.40.91).
Gregorio Paltrinieri would ordinarily have been favourite as defending champion and second fastest ever behind China's banned Sun Yang.
But the Italian was struck down with glandular fever in June, hampering his built-up, and he could only finish fourth.
US star Dressel wins 50m freestyle
Caeleb Dressel claimed his fourth Tokyo gold and earned the title of world's fastest swimmer Sunday with an Olympic-record 21.07 seconds in
the 50m freestyle final.
The American was untouchable in an event he has dominated in recent years, hitting the wall ahead of France's Florent Manaudou (21.55), who won gold at London in 2012 and silver at Rio 2016.
Brazilian Bruno Fratus (21.57) was third.
Dressel had his usual powerful start off the blocks and no one was going to stop him in the one-lap race as he continues to threaten Cesar Cielo's 2009 world record of 20.91.