At lunch on the third day Pakistan were 101 for two in their second innings, still 241 runs behind England's first innings 461 for nine declared, after Harmison and Panesar, who between them had taken nine wickets in the first innings, each added a further victim to their tallies.
But two of Pakistan's leading batsmen were at the crease with Younis Khan 34 not out and Mohammad Yousuf 15 not out.
Pakistan resumed on 12 without loss with Kamran Akmal two not out and Imran Farhat, batting with a fracture in his right ring finger, four not out.
Before play resumed Saturday fast bowler Harmison, who took six for 19 in Pakistan's meagre first innings 119, was passed fit after leaving the field late on Friday with a side strain.
Meanwhile wicket-keeper Geraint Jones continued behind the stumps despite suffering a fracture in the tip of his right ring finger while batting Friday.
Harmison though did not look in any discomfort during his first over Saturday, all of his initial six deliveries clocked in excess of 81 mph.
And in the fourth over, Harmison and Jones combined to take the first wicket of the innings.
Akmal, promoted to open after Salman Butt was dropped, was undone by a ball that lifted alarmingly just short of a good length.
Having got behind the ball rather than out of the way, it was all Akmal could do to fend it behind where Jones took a low, diving catch to dimiss his opposing gloveman for the wicket-keeper's second four of the match.
Pakistan were now 21 for one in the eighth over with Harmison on his way to a fiery opening spell of 7-2-10-1.
As the skies clouded over, England stand-in skipper Andrew Strauss brought left-arm spinner Panesar - who'd supported Harmison with three for 21 in the first innings - into the attack and he was soon getting sharp turn and bounce.
His accuracy was rewarded in his fourth over when Farhat, on 34, lunged forward with hard hands and gave a simple bat/pad catch to Ian Bell at short leg, Pakistan 60 for two.
In a match coinciding with the 50th anniversary of Jim Laker's record 19 for 90 at Old Trafford, another England spin bowler was playing an important, if not as dramatic, role in a Test at the Manchester venue and at lunch Panesar had fine figures of 9-1-18-1.
Harmison's first innings haul, on a lively pitch, saw England capitalise on the fact that, just as in the drawn first Test at Lord's, Pakistan were without leading fast bowlers Shoaib Akhtar (ankle), Mohammad Asif (elbow) and Rana Naved-ul-Hasan (out of the whole tour with a groin injury).
His return was then backed up by Alastair Cook (127) and Bell (106 not out) who batted England into a commanding position with their second successive Test hundreds after they'd each reached three figures at Lord's.
Left-hander Cook's hundred was the 21-year-old Essex batsman's third in seven Tests - a record unmatched by an England player since Ian Botham achieved the same feat in 1978.