Memphis never got off and running, couldn't pester Virginia into turnovers to start the break and couldn't knock down enough shots to set up its pressure.
All that sent the eighth-seeded Tigers to an opening-weekend loss in the NCAA tournament for the fourth straight season.
"We missed a lot of opportunities to set up our press because ... to set up a press, you've got to score," coach Josh Pastner said after Sunday night's 78-60 loss in the third round.
When the Tigers pushed the ball upcourt to take a quick shot, they often came up empty. Memphis shot 41 percent, went 3 of 13 from 3-point range and finished 9 for 21 on free throws. And the Cavaliers steadily capitalized on the Tigers' empty possessions, running off 10 straight points to take a double-digit lead on the way to a 35-20 halftime lead.
In a sign of how ineffective Memphis was in speeding up the tempo, 12 of its 18 fast-break points came in the second half after the Cavaliers had taken control. The Tigers also scored 17 fewer points than their season average.
"They've got to be the best defensive team I've ever played against in college," said senior leading scorer Joe Jackson, who finished with seven points. "They never lose sight of the basketball, and they just help each other out on every possession. You will never get an easy layup on them."
Joe Harris scored 16 points and the top-seeded Cavaliers shot 56 percent to earn their first trip to the NCAA tournament round of 16 in nearly two decades.
Anthony Gill added 13 for the Cavaliers (30-6), who turned in a dominating performance while controlling the tempo and shutting down the Tigers (24-10) at nearly every turn.
Virginia led by 15 at halftime and pushed that to 27 points late, picking right up where it left off in its strong finish to Friday's tournament-opening win against Coastal Carolina.
In what has already been the program's most successful season in decades, Virginia added another milestone: its first regional semifinal appearance since making it to a regional final in 1995. And the Cavaliers, carrying a No. 1 seed for the first time since the days of Ralph Sampson, look ready to go even farther.
Now they're headed to New York to face fourth-seeded Michigan State (28-8) on Friday night in the East Regional semifinals at Madison Square Garden.
On top of that, it's Virginia — not traditional powers Duke and North Carolina or league newcomer Syracuse — that stands as the Atlantic Coast Conference's only team still alive in the round of 16.
The reasons were all on display against a Memphis team eager to speed up the deliberate-paced Cavaliers and score in transition to avoid working against Virginia's stingy set defense.
Instead, coach Tony Bennett's team checked nearly everything off its to-do list, steadily overpowering the Tigers with confident efficiency.
The Cavaliers knocked down open looks. They played tough in the paint to contest Tigers drives. They patiently ran their offense to make Memphis defend deep into the shot clock, then snatched down every loose rebound when the Tigers missed chances to cut into the deficit.
There was no sign of the Virginia team that looked out of sorts while falling behind by 10 in the first half Friday against the 16th-seeded Chanticleers. Only the one that put Coastal Carolina away in the final 9 minutes.
Harris led the offensive effort that had five players scoring in double figures. Virginia also had a 40-28 advantage on the boards while backed by a loud crowd filled with Cavs fans who made the drive one state south for the start of Virginia's tournament push.
Austin Nichols scored 15 points to lead the Tigers.
Memphis came in looking for its first trip to the round of 16 since 2009, John Calipari's final year as coach before Pastner took over. The Tigers hadn't made it out of the opening weekend since, prompting senior guard Geron Johnson to promise shortly after the American Athletic Conference tournament that this year would be different.
Instead, Memphis again managed just one NCAA victory.
Follow Aaron Beard on Twitter at http://www.twitter.com/aaronbeardap