Only a stunning solo performance from goalkeeper Tim Krul saved Newcastle from a heavier defeat in their third-round tie.
Newcastle's caretaker boss Chris Hughton made it clear the Carling Cup was not his top priority when he named a side with just three players over the age of 23.
Hughton handed debuts to four youngsters and only Peter Lovenkrands and captain Steven Taylor remained from the side that defeated Plymouth in the Championship at the weekend.
It was a recipe for disaster for the Geordies and Peterborough, boosted by their first Championship win at the weekend, tore into United from the start.
Posh striker Aaron McLean hit the crossbar in the 10th minute but 10 minutes later the home side were in front thanks to some sloppy defending by the visitors.
George Boyd's corner rebounded to the Peterborough number 10 and when it cannoned back into the United six-yard area, Mackail-Smith was unmarked to head home from point-blank range.
Newcastle's youngsters offered little in reply and goalkeeper Krul was kept busy - saving from Toumani Diagouraga and turning a Boyd shot around the post.
But he was beaten again in the 31st minute when Ben Tozer gave the ball away and a shot from Posh left-back Tom Williams somehow squeezed in at the near post.
United continued to live dangerously and Mackail-Smith hit the bar again after a quick Posh counter attack left the visitors exposed at the back.
Seconds earlier United were unlucky not to earn a penalty when Williams appeared to foul Lovenkrands in the area.
Newcastle's woes continued in the second-half when Danny Guthrie was sent off for a second bookable offence.
He had already received a first-half yellow for kicking the ball away and he was given his marching orders for a foul on Boyd in the 54th minute.
Krul continued to keep the scoreline down with superb saves to deny Boyd and Mackail-Smith.
Peterborough's Dean Keates, on as a half-time substitute for Lee Frecklington, shot wide in the 70th minute when the midfielder only had Krul to beat.
Moments later a lighting raid from Peterborough's attack saw Krul deny McLean and Mackail-Smith before McLean's second effort was sent into the side-netting.
Newcastle sent on Alan Smith, Geremi and Kevin Nolan in a bid to get back into the tie but Posh goalkeeper Joe Lewis never had a save of note to make.
Indeed, Newcastle's Smith had to clear off the line from Craig Morgan as Peterborough continued to search for more goals.
Krul again denied the dangerous McLean with eight minutes remaining as the home side easily secured a place in the fourth round.