They fell behind after only 75 seconds and were 3-0 down by the 56th minute of the Championship clash.
And had it not been for Lilywhites goalkeeper Daniel Iversen, the Royals' lead would have been greater
However, North End made a fight of it, goals from Daniel Johnson and Cameron Archer cutting the deficit.
It set up an exciting closing spell but Lowe's men were unable to find a third goal to deliver a share of the spoils.
The only other two defeats of Lowe's reign had come on their travels, both in Wales against Cardiff in the FA Cup and in the league at Swansea.
Snow had to be cleared from the pitch before the game, it having started falling before dinnertime.
North End started badly and the first half didn't get much better from their point of view.
Fielding a side showing just one change from last week's 1-0 win at Peterborough - Scott Sinclair in for Josh Earl - they fell behind with just 75 seconds on the stopwatch.
A corner was cleared as far as the edge of the box where a stray Archer clearance gave possession back to Reading.
John Swift's low cross caused problems, Michael Morrison and Joao both had shots blocked by Iversen before Joao found the net the third attempt.
It was a lead doubled in the 19th minute, with North End producing little threat in between.
Swift's pass forward found Joao who had dropped deep, the Reading man turning and running at the PNE back line, before going past Patrick Bauer and finding the top corner with a right foot shot from just inside the box.
Ryan Lowe made an early tactical substitution, Liam Lindsay replacing Brad Potts in the 34th minute.
It saw a switch of a formation to 4-3-3, with Lindsay joining Bauer in the centre of defence - Sepp van den Berg and Andrew Hughes moving to the fiull-back roles.
They looked a little better for that in the closing stages of the first half, that said it needed a fine save from Iversen in the 37th minute to prevent them conceding a third goal.
A free-kick from the left channel was flicked over the PNE defence presenting Joao with a shooting chance in front of goal, Iversen throwing himself to his right to parry the striker's shot.
PNE's only chance of the first period came two minutes before half-time and it was a gilt-edged one too.
Good pressing from Sinclair on the right won them possession, his pass inside finding Emil Riis inside to the right of the goal.
He swung at it first time and lifted a left-foot shot into the stand.
Lowe made another change at the interval, Ryan Ledson coming on for Ben Whiteman.
Iversen produced three saves in the first five minutes of the second half as PNE failed to learn the lessons of the first period.
He dived to touch Swift's free-kick past the post, then saved at close quarters from Junior Hoilett, taking the power off the shot and allowing Hughes to clear off the line.
Then the Danish keeper dived to push away Joao's header after a corner from the left had come into the middle.
Lowe made his third and final substitution in the 53rd minute, that perhaps a measure of how things had gone - Ched Evans replacing Riis up front.
Before that change had any time to take affect though, Reading netted their third goal.
Swift took possession of the left and cut inside, playing a one-two with Joao on the edge of the box and collecting the return pass.
That put him behind the PNE defence and Swift lifted a shot over Iversen as he came off his line.
Within sixty seconds North End reduced the arrears, Evans found with a ball up the left channel which he knocked inside.
Johnson ran on to the knock down, took it to the edge of the box and hit a low shot which caught a deflection on its way past keeper Karl Hein.
The play swung from one end to another for a spell, PNE giving away a few needless free-kicks.
But things really got interesting in the 75th minute when they scored their second goal.
Ledson's corner from the right travelled to the far post, Hughes knocked it inside and in the ensuing scramble, Archer turned the ball home from inside the six-yard box,.
Sinclair went close to an equaliser four minutes later, running on to Alan Browne's pass and curling a left foot shot just over the bar.
North End piled on the pressure in the closing stages, Sinclair sending a header wide and Bauer seeing a shot blocked in the box.
Ultimately, they gave themselves too much to do. Although they have shown a resilience to fight back from losing positions plenty of times, doing so from three goals down was asking too much this time.
PNE: Iversen, van den Berg, Bauer, Hughes, Potts (Lindsay 34), Whiteman (Ledson 46), Browne, Johnson, Sinclair, Riis (Evans 53), Archer. Subs (not used): Ripley, Rafferty, Diaby, McCann.
Reading: Hein, Yiadom, Morrison, Holmes, Rahman (McIntyre 60), Rinomhota, Drinkwater, Ince (Barker 90), Hoilett (Meite 67), Swift, Joao. Subs (Not used): Southwood, Abrefa, Camara, Dele-Bashiru.
Referee: John Busby (Oxfordshire)
Attendance: 12,817 (332 away)