The tourists, playing their first Twenty 20 international, reached 148-5 with 13 balls remaining for a morale-boosting victory at Bristol.
Pakistan have a psychological edge going into Wednesday's five-match One-day series at Cardiff, while England have now lost their last eight limited-overs matches.
Typically explosive batting from all-rounder Shahid Afridi, with 28 from 10 balls, and a steady 46 from opener Mohammed Hafeez, saw Pakistan home.
Along with Hafeez, Afridi took 22 from Sajid Mahmood's first over and then 19 from Stuart Broad in the next over.
It proved a decisive passage of play as England never looked like recovering following Afridi's innings, which included five fours and a six.
Afridi eventually departed to an amazing catch by debutant Michael Yardy, who misjudged a slog over midwicket before diving backwards to take the catch.
Debutant Broad took two wickets in as many balls, after trapping Shoaib Malik lbw and having Younis Khan caught behind down the leg side first ball.
Facing the hat-trick ball, Afridi tried to hit Broad for six but his miscued slog instead went for two runs over the bowler's head.
All-rounder Abdul Razzaq (17 not out) clinched the match with two straight boundaries off Darren Gough. Skipper Inzamam-ul-Haq was 11 not out.
England, after winning the toss, began their innings solidly through Marcus Trescothick (53) and Ian Bell (14) but slumped from 39-0 to 50-4.
After fit-again Shoaib Akhtar had Bell caught, Mohammed Asif claimed two wickets in three balls and recorded the first maiden ever bowled in a Twenty 20 international.
Pakistan controversially forfeited the fourth test at the Oval after being penalised five runs by umpires Darrell Hair and Billy Doctrove for alleged ball tampering.
Inzamam, who ignored sporadic shouts of ''cheat'' from spectators, faces charges of illegally altering the condition of the ball and bringing the game into disrepute.