Irving battled a stomach virus earlier Wednesday but overcame the illness to score a game-high 28 points and dish out seven assists in a 106-96 loss to Golden State, dropping the Cavaliers (2-3) to 1-2 on their six-game trek.
Varejao, averaging 14.0 points and 15.0 rebounds, and Zeller both sat out after being injured in Monday's win over the Los Angeles Clippers. Varejao bruised his knee, Zeller sustained a concussion and broken cheekbone, and it's unclear when either will return.
Cleveland trailed by 16 at the end of the first quarter Wednesday and couldn't recover. Golden State shot 53.8 percent, and the Cavs are allowing opponents to hit 50.8 percent overall to rank last in the league.
"The first quarter was a prime example of coming out and almost feeling sorry for ourselves because we don't have Andy and Tyler," coach Byron Scott said.
"It was all about the defense, simple as that. Until our guys understand how important that is we're going to have these ups and downs."
Irving is averaging 24.6 points and 6.2 assists, though the reigning Rookie of the Year likely needs help from the team's other youngsters. Fellow 2011 lottery pick Tristan Thompson had 11 points and 10 rebounds Wednesday, and third-year player Samardo Samuels added 11 points and seven boards starting for Varejao. Rookie Dion Waiters had 12 points on 5-of-15 shooting after scoring 28 in the win at Los Angeles.
"We are talking about opportunity," Waiters said. "Andy had to miss a game and that gave other guys a chance to step up and play big for us. We did our best out there."
Irving scored 26 points in his only career game at Phoenix on Jan. 12, a 101-90 victory. He now faces a Suns team giving up 105.0 points per game -- second-worst in the NBA.
Phoenix (2-3), though, is coming off a 117-110 victory over Charlotte on Wednesday to avoid going winless on a three-game trip. Shannon Brown sank all six of his 3-point attempts in the fourth quarter while finishing with 24 points off the bench.
"I'm glad we're not going back 0-3 on this three-game road trip," Brown said. "Hopefully we can get a little bit of momentum going as we head back home."
Brown, a first-round pick of Cleveland in 2006 who appeared in 38 games for the Cavs, scored 18 points in a loss to Miami on Monday and is averaging 14.0 in a reserve role after averaging a career-best 11.0 last season.
"I think he's very capable of doing that," coach Alvin Gentry said. "He can get on a roll. He had some games for us last year. I thought he did a great job."
So did big men Marcin Gortat and Michael Beasley. Gortat had his fourth straight double-double with 23 points and 10 rebounds Wednesday while Beasley notched his first with 21 and 15, respectively.
Gortat and Markieff Morris each scored a game-high 22 points and Brown added 16 in Phoenix's 108-83 win over Cleveland in the most recent meeting March 25. The Suns have won three of the last four matchups.