Clijsters, bidding to become just the third mother to win a Grand Slam title in the modern era, saw off the challenge of China´s Li Na 6-2, 6-4. The Belgian had defeated Serena´s sister Venus in the fourth round.
The win over Pennetta was a fifth consecutive straight-sets win for Williams, who has been in imperious form as she seeks a fourth US Open crown and a 12th Grand Slam title overall.
The 27-year-old Italian, who has belatedly stepped out of the shadows this year to become the first woman from her country to break into the world top 10, gave as good as she got in the early exchanges against Williams.
She got to 4-4 before Williams started to turn on the power as and when she needed, holding serve easily and then break Pennetta´s serve to love.
The Italian did have two break points in the opening game of the second set but both times under pressure she netted a forehand.
The 10th seed, playing in just her second Grand Slam quarter-final, once again stood her ground valiantly until the sixth game when again Williams stepped on the turbo to force a break point on which Pennetta double-faulted.
That was all the American needed to set up the clash with Clijsters.
"She is such a great person and I only wish the best for her," Williams said of the Belgian, who only returned to tennis in early August after taking more than two years out to marry and have a baby.
"It will be a great match. She has nothing to lose and is having so much fun. It makes me so happy.
"Intitially I was surprised (how well Clijsters was doing on her comeback), but she did so well a couple of weeks ago that I knew she was someone to look out for."
Clijsters, who was given a wildcard to be able to compete at Flushing Meadows, dominated her match against Li apart from a spell in the second set when the Chinese No.1 won four games in a row to lead 4-3.
But the former world No.1 who won her only Grand Slam title here in 2005, promptly reasserted control to rattle off the next three games for the win.
"Obviously I feel good about it. It´s a nice feeling to have, knowing I was able to win it in two sets," Clijsters said.
"Even in that second set I got a little bit closer, but I was just able to finish it off in straight sets."
Turning to her semi-final opponent, Clijsters said: "Serena is a great athlete and a great girl and we always have some good laughs in the locker rooms and that´s what makes it fun as well."
The win and semi-final place meant Clijsters equalled the best recorded run by a wildcard, man or woman, at the US Open, matching Jimmy Connors in 1991.
The defeat was a heavy blow for Li, who was bidding to become just the second Chinese player ever to reach a Grand Slam semi-final, matching Zheng Jie´s wildcard run into the Wimbledon last four in 2008.
It was Clijsters who also stopped Li the last time she reached a Grand Slam quarter-final at Wimbledon 2006.
The two remaining quarter-finals will be played on Wednesday in a half of the draw where only one seed made it through to that stage.
In a clash of two unseeded players, Yanina Wickmayer of Belgium will play Kateryna Bondarenko of Ukraine, while 17-year-old American sensation Melaine Oudin will take on Danish ninth seed Caroline Wozniacki.
Nadal rises while Murray stumbles
Meanwhile in men´s section, Rafael Nadal assured a jump past Britain´s Andy Murray back into the world number two ranking by advancing to the US Open quarter-finals Tuesday while the Scotsman crashed out in humbling fashion.
Spanish third seed Nadal, trying to complete a career Grand Slam with a seventh major title, defeated French 13th seed Gael Monfils 6-7 (3/7), 6-3, 6-1, 6-3 to book a spot in the last eight against Chilean Fernando Gonzalez.
"He´s a very good player," Nadal said. "If I don´t play my best it´s going to be impossible."
Nadal showed no sign of pain after a two-month layoff with knee tendinitis, calling his knees "very good", or from a right abdominal muscle injury that was treated during his third-round victory Sunday over countryman Nicolas Almagro.
"I had a few problems but I am in the quarter-finals here for the third time and I´m very happy," Nadal said. "I´m just trying to enjoy my comeback. It´s a big result for me. It´s much better than what I expected."
A spectator, camera in hand, ran onto the court moments after the match and reached Nadal to give congratulations before security guards pulled him away.
Nearly as shocking as the surprise intruder was Murray´s fourth-round exit, the second seed never looking on form as Croatian 16th seed Marin Cilic reached his first Grand Slam quarter-final with a 7-5, 6-2, 6-2 victory.
"I just struggled," Murray said. "I played poorly. I´m very disappointed. I didn´t feel like I played well. I had my chance in the first set and struggled after that."
The 22-year-old who was last year´s US Open runner-up failed in his bid to become the first British men´s Grand Slam champion since Fred Perry in 1936.
"The way the match went makes it disappointing but I believe I will come back better from it," Murray said. "I will learn from this week like I have most weeks when I´ve lost and I will come back better and stronger.
"I think I will be a better player next year than this year."
Cilic will play for a semi-final berth against Argentine sixth seed Juan Martin Del Potro, who fired 22 aces and 44 winners to defeat Spanish 24th seed Juan Carlos Ferrero 6-3, 6-3, 6-3.
"I have my confidence in the best moment," Del Potro said. "I´ve beaten many good players on this surface. I would like to be in the semis or my first final. I have everything to do it."
Gonzalez, the 11th seed, advanced past French seventh seed Jo-Wilfried Tsonga 3-6, 6-3, 7-6 (7/3), 6-4. Gonzalez, trying to become the first South American man to win the US Open in 32 years, is 3-6 lifetime against Nadal.
"I have a lot of confidence," Gonzalez said. "I have to be worrying about myself only and try to play my best tennis."
Gonzalez, the 2007 Australian Open runner-up in his best Slam showing, had not reached the US Open final eight since his 2002 maiden Slam quarter-final appearance but denied Tsonga on 13-of-14 break-point chances to advance.
Nadal is trying to become just the seventh man to complete the career Grand Slam, joining Roger Federer, Andre Agassi, Fred Perry, Don Budge, Rod Laver and Roy Emerson as the only men to win each of the four major titles.
Monfils won five of the last six points in the tie-break but was undone by 63 unforced errors. Nadal broke twice to claim the second set, three times including the first and last games to take the third.
Nadal and Monfils exchanged breaks in the fourth and fifth games of the last set but the Frenchman double-faulted away a break in the eighth game and Nadal held to win after two hours 45 minutes.
In taking his first victory over a top-three opponent in seven attempts, Cilic fired 10 aces and 35 winners while Murray went 0-for-7 on break-point chances and made 41 unforced errors.
"I played very well and he was missing a lot," Cilic said. "I don´t think he was playing his best."
Defeat on the Flushing Meadows hardcourts was especially stinging for the 22-year-old Scotsman, who loves the surface as well as the atmosphere of a New York fortnight in the year´s last Grand Slam event.
"I returned poorly. He served well. That felt like the difference," Murray said. "The momentum was with him and I didn´t manage to get it back.
"I´m disappointed. I don´t know how long or how quickly it will take me to get over it."
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