Harmison had figures of three for 14 in seven overs, including a spell of two wickets for no runs in eight balls, as England dominated the first session in the second match of a four-Test series.
The Durham quick's early double strike left the tourists nine for two after Pakistan captain Inzamam-ul-Haq won the toss and batted here on Thursday.
After Mohammad Yousuf (38) and Younis Khan (44) repaired the early damage with a stand of 81, left-arm spinner Monty Panesar struck with his fourth ball to dimiss Yousuf.
And Harmison, with the first ball of his new spell and in the last over before lunch, returned to see off Younis.
At the interval Inzamam was nought not out and Faisal Iqbal three not out.
England's chances of an early breakthough were increased when Pakistan, with Shoaib Malik still unfit, again reshuffled their opening combination.
Wicket-keeper Kamran Akmal was promoted up the order in place of dropped opener Salman Butt with vice-captain Younis, fit again after a knee injury, in at number three.
Matthew Hoggard began with a testing first over, making the ball cut sharply off the pitch.
But it was the quicker Harmison who struck first when Imran Farhat fell for nought in the fourth over after the left-handed opener, pushing tentatively forward, was caught at deep gully by Kevin Pietersen.
And in the sixth over Akmal went for just four when he edged Harmison and Marcus Trescothick took the catch despite wicket-keeper Geraint Jones diving across him at first slip.
Harmison had often been wayward in the drawn first Test at Lord's but such was his accuracy Thursday he did not concede a run until his fourth over.
Pakistan's start was even worse than it had been at Lord's, where they had been 28 for two, and once again their senior batsmen had to repair the damage.
But now Yousuf, whose 202 at Lord's was his second double century in as many Tests against England, was at the crease alongside Younis.
After an impressive opening spell of 6-3-11-2, Harmison was replaced by Sajid Mahmood, in for the injured Liam Plunket, who started with a fiery maiden.
But Younis then turned Hoggard off his legs for four before Yousuf casually eased Mahmood to the cover boundary.
From the next ball Yousuf, on 16, saw a diving Alastair Cook at gully narrowly fail to hold to a difficult chance from a flashing drive off Mahmood.
England's back-up seamers were now largely struggling to maintain the early pressure on a lively pitch.
But Panesar restored England's morale when he had Yousuf caught behind by Jones after the batsman had faced 58 balls with six fours.
And three balls later Younis - who also struck six boundaries - fell when he was well caught by Paul Collingwood in the gully off a forcing shot.