The second-seeded Williams reached the semifinals for the sixth straight year.
Williams, 22, will face France's Amelie Mauresmo in the final four on Friday. Mauresmo battled to a 4-6, 7-6 (7-5), 6-3 victory over third seed Jennifer Capriati of the United States.
On the men's side, top seed and defending champion Lleyton Hewitt of Australia also reached the semifinals, working his way past the weary 20th-seeded Younes El Aynaoui of Morocco, 6-1, 7-6, 4-6, 6-2.
Hewitt will meet No. 6 Andre Agassi in what could be a classic semifinal duel. Agassi rallied Wednesday night to defeat No. 32 Max Mirnyi of Belarus, 6-7 (5-7), 6-3, 7-5, 6-3.
Williams survived a three-set duel against fellow American Chanda Rubin to reach the quarterfinals. She was not about to allow Seles the same opportunity.
On the lone break point against her serve, Williams unleashed an ace at 112 miles per hour and deflated Seles' spirit.
"I think my first-serve percentage is just higher (than against Rubin) and I was able to get a lot of pace on the first serve," Williams said. "Even on the second, I was able to get a lot of kick, so it was bouncing high."
Williams improved to 8-1 lifetime against Seles. She also defeated Seles in straight sets at the French Open after losing for the only time in their quarterfinal matchup at the Australian Open.
Williams is trying to become the first woman to win three straight U.S. Opens since Chris Evert did so from 1975-78.
The winner of nine Grand Slams, including a pair of U.S. Opens, Seles had no answer for Williams' power.
"She just served too well," Seles said. "I really couldn't read it at all. It was too strong."
The 10th-seeded Mauresmo, 23, became the first French woman to reach the U.S. Open semifinals.
Mauresmo almost made a quick exit as Capriati served for the match in the second set. But Mauresmo broke to force a tiebreaker, won it, then broke Capriati twice in the final set to reach the semifinals here for the first time.
"She has a different style of game," Capriati said. "She mixes things up. She's a good mover around the court. But I think today I should have won that match. It hurts. It definitely hurts. I had that match."
Mauresmo beat Capriati for the third straight time. Her victory Wednesday marked the first time this year that Mauresmo had won a match after losing the first set.
The players had to contend with the heat and humidity for more than two hours and Mauresmo had more left at the end.
In the second set, Capriati broke to go ahead, 6-5, and served for the match. But she fell apart, making four unforced errors, including a double fault. Capriati took a 3-2 lead in the tiebreaker but lost the next two points on her serve and was unable to recover.
In the third set, Mauresmo broke in the third and ninth games. The final game went to deuce five times and Capriati held off four match points before a forehand sailed long to end it.
"When you're down a set and 6-5 and she's serving, you have to hang in there, even though you're thinking maybe it's the last game," said Mauresmo. "You still have to hang in there and try to do your best. That's what I did and it worked out pretty well.
"I know she doesn't like to play against me. Maybe she gets a little bit tight when she has to play against me. I've beaten her a few times (four of seven matches). My game is a little bit different from the other players on the tour. Maybe she's just not used to that so much."
Capriati, still visibly angry an hour after the match, said she simply succumbed to the pressure.
"I had a chance to close out the match and I didn't," she said. "I wasn't playing with the same kind of loose shots that I was playing before. I felt kind of tight out there the whole time. I came out and I was pretty nervous. Getting tight is basically saying you choked."
El Aynaoui had been forced to play into the early morning hours Tuesday to reach the quarterfinals and was sluggish in the opening set as Hewitt breezed through at 6-1.
After pulling his game together in the second set, El Aynaoui was broken at 5-4 and wasted another set point in the tiebreaker, which Hewitt closed out with a backhand crosscourt winner.
The first Moroccan to advance to the quarterfinals, El Aynaoui had his best moment late in the third set when he broke Hewitt in the final game. But Hewitt dominated the fourth set, breaking twice and cruising to the win.
Hewitt is trying to become only the seventh man in the Open era to win back-to-back titles and the first since fellow Australian Pat Rafter did it in 1997-98. Hewitt also is looking for his second consecutive Grand Slam title after taking the Wimbledon crown.
Appearing in a Grand Slam quarterfinal for only the second time, El Aynauoi fell to 1-3 all-time against Hewitt. The 30-year-old El Aynaoui is having the best year of his career. Three of his five career titles have come this year and he lost in the finals of two other events.