Once a candidate for a top-two finish, the Eagles now find themselves just three points above seventh-placed Bolton, albeit with a game in hand, after the loss at Portman Road extended their winless streak to six matches.
Despite having 30-goal frontman Glenn Murray in their ranks, Palace have now failed to find the net in their last five outings.
The visitors' lack of confidence in front of goal were evident early on as Jonathan Parr had an effort deflected wide and Kagisho Dikgacoi fired over.
The Tractor Boys responded and Nouble shot wide before Jay Emmanuel-Thomas also failed to hit target from 30 yards.
But the hosts went ahead eight minutes before half-time after a huge error from Julian Speroni. The usually reliable shot-stopper tried to control a long ball on his chest outside his area, but failed to clear the danger and Nouble stroked the ball into the empty net.
Things got worse for Palace in first-half added time as Ipswich struck twice to race into a 3-0 lead.
Guirane N'Daw's cushioned header found its way to Cresswell, who fired an unstoppable left-footed effort from 30 yards into the top corner.
Nouble then heaped more misery on Palace when he capitalised on poor defending to slot past Speroni for his second of the night.
Palace desperately searched for a way back in the game after the break and finally tested Scott Loach, with the goalkeeper having to push away Andre Moritz's free-kick, while Wilfried Zaha had a shot deflected wide.
Holloway tried to inject his struggling team with more attacking options with 22 minutes to go by bringing off defender Joel Ward for forward Aaron Wilbraham.
And that change seemed to bring Murray to life when he tested Loach with a shot from the edge of the area.
But Ipswich were keen to add a fourth and Speroni had to be alert to save Luke Hyam's 12-yard shot after good work from Nouble.
Murray almost broke his team's duck but Loach stood firm before substitute Kevin Phillips hit the post in added time.