Despite a lot of good play from Latics, they were caught on the break on 66 minutes as substitute Eoin Doyle opened the scoring.
Jordan Hugill made it 2-0 with only 10 minutes of the game remaining as Latics exited the competition at the second round stage.
Steve Robinson elected to make three changes to the side which beat Bury on Saturday.
Out went Billy Mckay, who missed the game with a slight injury, Paul Green and Ryan Flynn and in came Brian Wilson, Ollie Banks and Jake Cassidy.
It would be Cassidy who caused a threat in the opening couple of minutes of the game, winning headers and he won a corner in the third minute which Preston just managed to clear.
The next team to go close was the home side as Hugill headed Ben Pringle’s cross goalwards but Connor Ripley kept the ball out and dived on the rebound.
Latics almost took the lead on 18 minutes as Josh Law found Marc Klok alone in the middle but his touch took him away from goal and his shot was tame and was cleared.
Whilst the Lilywhites threatened in attack, Latics were as solid as ever at the back with Peter Clarke marshalling the defence well.
Behind him was Ripley who was out to claim everything which came into the box in the first half, as well as he did at the weekend.
Just before the half hour mark, Pringle was forced off after picking up an injury earlier in the game and he was replaced by Alan Browne.
He almost made an immediate impact on the game but struck over from the edge of the box after the ball fell to him.
Latics’ best opportunities of the half came from set pieces with Klok’s delivery proving to cause problems for Preston North End.
Banks had two chances to put Latics ahead 10 minutes before the end of the first half as he struck over from inside the box before mis-kicking on the edge from Klok’s corner.
Latics had to be wary with five minutes of the half remaining as Ousmane Fane gave away a free kick right on the edge of the box.
Hugill stepped up for North End but blazed his effort over the crossbar as we went into the half time break goalless.
Robinson made a change at half time and brought on experienced midfielder Paul Green for Klok.
That move almost paid off for Latics as Green picked out Cassidy’s run early into the second half but Preston goalkeeper Chris Maxwell was off his line quickly to head away the danger.
Erwin almost gave Latics the lead five minutes into the second half as he danced across the penalty area and his strong drive was saved by the goalkeeper.
Just before the hour mark, the striker did exactly the same thing as he unleashed a fierce strike from the edge of the box but Maxwell beat the ball away.
That was only cleared as far as Law on the right who teased a cross along the six yard box but nobody could get on the end of it for Latics.
Simon Grayson made changes and brought on Doyle and Robinson who injected pace into the game.
That move would prove a good one for the home side as Doyle collected the ball in the penalty area and despite the best efforts from the defence, he rolled the ball into the bottom corner to give North End the lead.
Prior to the goal, Latics had been putting pressure on the Preston North End back line and that continued despite going a goal down.
Robinson brought on Ryan McLaughlin and Darius Osei with 20 minutes remaining and the latter almost made an immediate impact.
He got beyond his man on the right but could not pick out an Oldham Athletic man in the penalty box as he showed positive glimpses.
Whilst Latics still continued to press forwards, they were again caught on the counter attack as Preston extended their lead 10 minutes from time.
Ripley was caught on the left, Doyle capitalised and crossed towards the back post and Hugill headed into the back of an empty net.
Erwin was booked in the final few minutes of the game as he prevented a breakaway from the home side but Latics fell to defeat in the second round of the EFL Cup.
Preston North End: Maxwell, Cunningham, Pearson, Clarke, Humphrey, Makienok (Doyle 60’), Spurr, Pringle (Browne 27’), Welsh (Robinson 60’), Huntington, Hugill.
Subs not used: Hudson, Johnson, Grimshaw, Davies.
Oldham Athletic: Ripley, Law (McLaughlin 67’), Wilson, Burgess, Clarke, Dunne, Fane, Klok (Green 46’), Banks (Osei 69’), Erwin, Cassidy.
Subs not used: Kettings, Edmundson, Flynn, Croft.
Goals: Preston North End (Doyle 66’, Hugill 81’) 2-0 Oldham Athletic
Attendance: 5,075 (751 visiting supporters)