The former Liverpool striker, 26, stuck with a fine header in the 27th minute of Saturday's Championship clash at Deepdale and substitute Stephen Elliott added a late second to ensure the Swans' worst start to a season for seven years continued.
For in-form Preston - now undefeated after six games - the result went some way towards avenging the league double Swansea did over them last season.
Back then the Welshmen were riding high in the Championship and looking capable of mounting a serious promotion challenge.
Yet since Roberto Martinez's defection to Wigan, and Paulo Sousa's subsequent appointment as his successor, they have struggled badly and offered next to nothing at Deepdale.
A goal threat was seriously lacking and the withdrawal of the ineffective Lee Trundle, back at the Liberty Stadium on loan from Bristol City, after just 57 minutes said everything.
Swansea fashioned the first clear-cut opening in the 18th minute which should have led to the opening goal.
A typically intricate passing move saw Andrea Orlandi break from just inside the North End half and find Nathan Dyer with a neat pass.
He kept the ball moving with a swift pass out to midfielder Mark Gower, lurking unmarked just inside the penalty area.
Gower lined up a low left-footed shot but an excellent stop from Preston goalkeeper Andy Lonergan saw the ball deflected over for a corner.
Nine minutes later, Preston led when Swansea failed to clear a free-kick and Chris Brown hooked the ball back in for Mellor to send a stooping header into the net from six yards.
The goal breathed confidence into Preston and former Cardiff winger Paul Parry showed brilliant skill to beat his man down the right flank and hit a vicious cross-shot which required a fine parried save from the outstanding Dorus De Vries.
North End went close doubling their advantage after the break when Mellor and Brown threatened with headers.
Yet Swansea looked slightly more dangerous following the arrival of substitutes Craig Beattie and former Ajax midfielder Cedric Van der Gun.
Beattie - Trundle's replacement - hit a low shot from distance which drew a smart stop from Lonergan in the 70th minute.
De Vries made a stunning save to keep his side in the game in the 77th minute when he palmed away Billy Jones' powerful header from a cross by substitute Chris Sedgwick.
However, he was powerless to prevent Preston claiming their second goal with a minute remaining when Sedgwick brilliantly cut the ball back from the right for Elliott to rifle the ball high into the net from six yards.