Adrian won his heat in 48.19 seconds while swimming in a lane next to world-record holder Cesar Cielo of Brazil.
"It felt good to be that easy in the first 50 and to have a little bit to come home," Adrian said. "Maybe I can go faster, who knows?"
Phelps already has the most gold medals of any Olympian - 14 - and eclipsed Mark Spitz's record with eight wins in Beijing four years ago.
Now he could tie Soviet gymnast Larisa Latynina's record of 18 career medals in the 200 butterfly final, and he would own the mark outright if the U.S. makes the podium in the 4x200 freestyle relay.
Phelps had the morning off while his teammates qualified the U.S. first in the relay heats.
In the 100 free, Cielo, the 2008 bronze medalist, tied for 10th with Konrad Czerniak of Poland in 48.67. Cielo's time was well off his world mark of 46.91 set at the 2009 world championships during the peak of the high-tech body suit craze. Those suits have since been banned.
"It felt a little heavy, actually," Cielo said. "But hopefully tonight I'm going to bring some heat and I'll swim better to make the final."
Gideon Louw of South Africa was second-quickest in 48.29, followed by Sebastiaan Verschuren of the Netherlands in 48.37.
World champion James "The Missile" Magnussen of Australia advanced in fourth at 48.38. No other swimmer in a textile suit has gone faster than the 47.10 he posted at his country's trials in March.
But Magnussen's opening leg of the 4x100 freestyle relay on Sunday raised some doubt about whether he can add the Olympic title to his world championship. The Aussies were favored but wound up off the medals podium in fourth.
"I took a fair hit in the relay. I am still trying to bounce back from it," he said. "It hurt my pride as much as anything else. A lot of my competitors have never seen me lose."
Adrian swam the leadoff leg for the Americans in 47.89, going out faster than Magnussen to give the U.S. an early lead. The U.S. settled for silver after Ryan Lochte was caught on the final lap by Yannick Agnel of France.
"It wasn't that I was nervous. I just got too worked up over it," Magnussen said. "I just need to stay relaxed and be confident. They probably think they can beat me, but I am going to fight for this one."
Cielo wasn't ready to write off the Aussie.
"That was one mistake. You can't put those guys out of contention," he said. "I think James is still one of the favorites. I would put him and Agnel down as hands-down the favorites."
Adrian agreed with Cielo, saying that a full day's rest could make a difference.
"They got those first-race jitters out of them and now I would not doubt that they're a lot faster and a lot tougher in the individual," Adrian said.
Agnel tied James "The Rocket" Roberts of Australia for 12th in 48.93.
"I didn't sleep much last night," said Agnel, who won the 200 free on Monday. "I feel like an alien. I knew it would be tough to do but I have got all day to recover."
