At stumps, on the second-day of the four-match series, Pakistan were 66 for three in reply to England's first innings 528 for nine declared, a deficit of 462, after Paul Collingwood had made a Test-best 186 and Ian Bell 100 not out.
Pakistan, left with a tricky 19 overs between the declaration and the close, lost opener Salman Butt (10) when the left-hander edged a drive off Harmison to England stand-in captain Andrew Strauss at second slip.
Two balls later Faisal Iqbal, confronted with a delivery that rose sharply, saw Collingwood take a brilliant leaping one-handed third slip catch off Durham team-mate Harmison, who had two for 15 from eight overs at stumps.
The tourists were now faltering at 28 for two.
Then Liam Plunkett, the third Durham man in England's XI, got in on the act with his 11th ball when he bowled opener Imran Farhat for 33 with a ball that clipped the left-hander's off-stump.
Mohammad Yousuf was 20 not out at stumps and nightwatchman Mohammad Sami unbeaten on nought, with Pakistan still needing a further 263 to avoid the follow-on.
Earlier all-rounder Collingwood shared a record England fourth-wicket stand of 233 against Pakistan with Alastair Cook, whose 105 was also his Test best, before putting on 120 with Bell as England capitalised on their strong overnight position of 309 for three.
"It was nice to contribute. I said before the start of play that we set it up yesterday and it was up to us to go on and get big scores," said Bell.
"I was disappointed to be left out for the Sri Lanka series (earlier in the summer) because I want to be big part of the England set-up.
"I enjoy playing a part but we've got big squad and it will be interesting to see what happens if people come back for the next game.
"I've come in for this series and I've got to make the position my own. I've got an opportunity with Freddie (Flintoff) injured and I have to show I'm good enough to play at this level"
Leg-spinner Danish Kaneria, who took two wickets for no runs in seven balls in a spell before tea, fin
"It was really hard work and it's going to be similiar wherever we play in this series because it will be very hot," said Kaneria.
"I'm ready to bowl as many overs as neccessary but I want to get the wickets as soon as possible."
Bell, recalled in the absence of injured all-rounder Andrew Flintoff, got off the mark with a streaky four down to third man off Sami.
But from then on the 24-year-old, still trying to secure a place in the England side, looked assured in a chanceless innings as he went to his third Test hundred and second against Pakistan after 115 at Faisalabad in November.
At tea, England were 495 for seven with Bell 75 not out and Matthew Hoggard unbeaten on eight.
Hoggard though was lbw to leg-spining all-rounder Shahid Afridi for 13, with Bell 11 runs shy of his hundred
Then Harmison, trying to give Bell the strike, was run out for two by Yousuf's throw to Afridi.
That left Bell on 97 with only last man Monty Panesar for company.
But Panesar held firm for a six ball nought not out before Bell turned Afridi legside for the single that took him to a 168-ball century, including nine fours.
Earlier Collingwood, strong through the offside, was within four runs of his career-best total when he was stumped by wicket-keeper Kamran Akmal after lunging at a Kaneria delivery that beat the outside edge.
He faced 327 balls with 23 fours, England 441 for five.
Collingwood's seven-and-a-quarter hour innings was the best by an England batsman against Pakistan at Lord's, surpassing Tom Graveney's 153 in 1962.
England resumed Friday with left-hander Cook 101 not out, dropped on nought and three times in all, and 30-year-old Collingwood - missed on 79 - unbeaten on 109.
The pair had both scored their second Test hundreds and first at home, after they'd each reached three figures against India at Nagpur in March.
Poor fielding was the last thing Pakistan needed after they'd been forced to do without lead fast bowlers Shoaib Akhtar (ankle), Rana Naved-ul-Hasan (groin) and Mohammad Asif (elbow).
But Sami took the fielders out of the equation by clean bowling Cook off-stump. The Essex batsman faced 279 balls with 10 fours in an innings lasting more than for five hours.
England 1st Innings (overnight: 309-3)
Fall of wickets: 1-60, 2-60, 3-88, 4-321, 5-441, 6-469
7-473, 8-515, 9-525
Pakistan 1st Innings
Fall of wickets: 1-28, 2-28, 3-65
To bat: Inzamam-ul-Haq, Abdul Razzaq, Shahid Afridi, Kamran Akmal, Umar Gul, Danish Kaneria
Umpires: Steve Bucknor (WIS), Simon Taufel (AUS)
TV umpire: Peter Hartley (ENG)
Match referee: Ranjan Madugalle (SRI)