The Giants started backup Ryan Nassib in Manning's place, and in addition to their two-time Super Bowl MVP quarterback, Cruz (groin), linebacker Keenan Robinson (groin) and defensive end Kerry Wynn (groin) were inactive.
Shepard looked good in his first preseason game.
The New York Giants, after a hot start, committed four turnovers and lost their preseason opener to the Miami Dolphins 27-10. After a smooth first 15 minutes, Nassib turned the ball over three times in the second 15 en route to a 27-10 loss.
Miami had nine penalties for 61 yards and one turnover.
A 3-yard run by Rashad Jennings and a 20-yard field goal by Josh Brown following an interception by Jonathan Casillas staked NY to its first-quarter lead.
On second down, prized defensive end Olivier Vernon, playing against his former team, beat Dolphins left tackle Branden Albert with a speed rush inside and decked quarterback Ryan Tannehill as he threw incomplete.
The first, an interception by Bobby McCain, would set up a 49-yard field goal by Andrew Franks. On the Giants' next possession, Nassib fumbled the ball, which was returned by Spencer Paysinger and lead to a 5-yard touchdown run by Damien Williams.
Third-string quarterback Logan Thomas didn't fare much better in the ball security department as his fumble in the fourth quarter led to a 16-yard touchdown by Zac Dysert to Thomas Duarte on fourth down. Moore was 10 of 14 for 122 yards and a touchdown. Sixth-round pick Jakeem Grant had four catches for 68 yards.
First-round pick Apple was diagnosed with a lower-leg strain after undergoing X-rays, which were negative.
It's too early to tell if Cruz will be able to play in the Giants' second preseason game at Buffalo on Saturday. Apple, Shepard and S Darian Thompson are all going to contribute, along with Major League Baseball B.J. Goodson, who had seven tackles, including two for losses.
The late start and the pre-game rain dropped the temperature to 76 degrees at kickoff. While he would have Odell Beckham Jr. and the first team offensive line if he entered a real game, he still made some mistakes that go beyond the players that surrounded him.
Apple admitted that he was nervous when he first felt his injury since he had never before hurt his knee. Veteran Victor Cruz was already out with a groin injury.
"When I've got single man coverage, I've just go to put a little more air under it and let those guys run underneath it", Nassib said.
Added Pierre-Paul: "We have a lot of work to do, a lot of work".