Sevastova has gone three sets in three of her first four matches, including a roller-coaster fourth-round victory over seventh-seeded Elina Svitolina.
Isner's bid to become the first American man in a dozen years to get to the final four at Flushing Meadows ended Tuesday with a 6-7 (5), 6-3, 7-6 (4), 6-2 loss in Arthur Ashe Stadium to No. 3 seed del Potro, the Argentine who won the 2009 championship.
Many players have been driven to distraction by the small margins involved when playing Isner and one backhand that just drifted into the tramlines cost Del Potro the opening set - the first set he has lost all tournament. In an nearly irrational, inexplicable eighth game, the Latvian missed two opportunities but Stephens failed to hold despite her seventh forehand victor of the set. "The heat doesn't make it any more fun".
With temperatures hovering above 32.2 degrees Celsius and the tournament's extreme heat policy in effect for a second consecutive day, Sevastova broke an error-prone Stephens to go ahead 3-1.
She then dropped her racket and held her hands to her face as a Stephens shot went into the net on the match's final point.
"I saw that she was struggling. I think that's what happened today", said Stephens, who said she has been suffering from a sinus infection. I was struggling also a little bit, but I didn't show it that much.
Sevastova, the No. 19 seed, played an unbelievable match to leave Williams and Madison Keys as the only two American women remaining.
The popular Argentinian will now attempt to take a step he has not managed since winning his only grand slam title here nine years ago and reach another final.
"I could have [lost] in the first round, and that would have been really bad", she said, invoking some colorful imagery in the process.
Despite failing in her bid to become the first woman to retain a grand slam title since Williams triumphed at Wimbledon in 2015 and 2016, Stephens was still happy with her performance at Flushing Meadows.
In among the wrist surgeries and long lay-offs, Del Potro has made three semi-finals, losing to Novak Djokovic at Wimbledon in 2013 and then Rafael Nadal here previous year and at the French Open this summer. "I'm just going to try to play the rest of the season as hard as I can and hopefully have some more good results".