Hewitt was broken for the first time when serving for the match at 5-4 in the third set Thursday. The Australian broke right back but double-faulted on his first match point in the next game. But del Potro then sent a shot long to give Hewitt a 6-3, 7-5, 7-5 win. The 2002 champion and former No. 1 saved all six break points he faced in the first set.
Hewitt broke an 11-match losing streak against top-five players.
"Oh, it was a big win. I wanted to beat a top-five guy," Hewitt said. "These are the places you want to do it, too."
Del Potro is the highest men's seed to lose so far in the tournament. He also lost in the second round the previous two years at Wimbledon.
"You know, he's one of my idols," del Potro said of Hewitt. "I start to follow him when I was young, like 11."
Hewitt was cheered on by a group of Australian fans on Centre Court.
"I heard there was a few of them sleeping over last night to get some tickets out here to come in today. I appreciate the crowd," Hewitt said. "I love playing in London. I love playing in England. It's a lot of fun for me. It feels like a second home, really."
Murray saved two break points early in the first set but never faced another against the Latvian, winning 6-2, 7-5, 6-3 in front of a packed Centre Court. He hit 36 winners with just five unforced errors.
"I thought I played well," Murray said. "Served really good for the whole match. Apart from the very first game where he had a couple of chances on my serve, I didn't give him another break point.
"I used my variety very well. It was much, much better than the first match," he said.
Murray is trying to become the first Brit since Fred Perry in 1936 to win the grass-court Grand Slam tournament.
"It was comfortable most of the time," Roddick said. "I played my best set by far in the fourth set."
Playing on sunny Court 1, the No. 6-seeded Roddick hit 18 aces and lost serve only once. He'll next play No. 26 Jurgen Melzer, the Wimbledon boys' champion in 1999. Roddick has won their eight previous meetings.
"We're pretty even from the baseline. I can even say I might have a little edge on him," the 39th-ranked Kunitsyn said. "But his serve is a big advantage on these courts."
Roddick, one of only three American men left in the tournament, was runner-up to Roger Federer at Wimbledon in 2004-05. Roddick has 65 grass-court wins, second only to Federer among active men.
Fellow American Jesse Levine reached the third round by defeating Pablo Cuevas of Uruguay in five sets. Levine, of Boca Raton, Fla., won 6-2, 6-1, 4-6, 4-6, 6-3. He had never advanced past the second round at any Grand Slam tournament.
The 21-year-old Levine is ranked 133rd and is the last qualifier left in the men's draw.
Levine entered Wimbledon with an 0-2 record in tour-level matches in 2009. But he upset two-time major champion Marat Safin in the first round before getting past the 125th-ranked Cuevas, who lost in qualifying but got into the main event when someone withdrew.
"He goes about it the right way. He's professional. He works hard," Roddick said about Levine. "You wish all the young guys kind of had his work ethic and professionalism."
No. 8 Gilles Simon, No. 10 Fernando Gonzalez, No. 12 Nikolay Davydenko, No. 16 David Ferrer, No. 19 Stanislas Wawrinka, No. 20 Tomas Berdych, No. 23 Radek Stepanek, No. 30 Viktor Troicki and No. 31 Victor Hanescu also advanced.
Fabrice Santoro's 14th and last Wimbledon ended with a 6-7 (1), 6-3, 6-4, 6-3 loss to Juan Carlos Ferrero. The 36-year-old Frenchman was playing in his record 68th Grand Slam tournament and 44th consecutive major but has said he is retiring at the end of the year.
Ferrero won the French Open in 2003 and is a former No. 1, but the Spaniard was given a wild card to the tournament in May after slipping outside the top 100.
Santoro and Vince Spadea are tied for the most appearances among the men at this year's Wimbledon.
Information from The Associated Press and Reuters was used in this report.