Paul Coughlin reached a double century to help Durham edge close to the Second XI Championship on the second day of the final at the Emirates Riverside.
Usman Arshad then took command with the ball – including three wickets in one outstanding over – to restrict Middlesex to 194-8, a deficit of 310.
Coughlin was 179 not out at the close on day one and was last man out in Durham’s first innings, falling to a run-out by James Fuller for a memorable 231, off 276 balls, with 28 fours and two sixes.
Durham added 96 runs to their overnight total to finish on 504 all out, with Eddie Hurst hitting 36
Middlesex never looked comfortable in their response and found Arshad in irresistible form.
He plundered 4-34 in 14 overs, including opener Paul Stirling lbw for 10.
The visitors lost wickets at regular intervals, with a partnership of 48 for the fourth wicket, between Max Holden and George Scott, lifting them from 43-3 to 91-4.
Three wickets fell without scoring when Middlesex were on 106, with Arshad grabbing all three in the same over.
With his second ball of the over, Arshad clean bowling Scott for 26.
Two balls later, Dom Manuwelge was trapped lbw for nought, then, with the very next delivery, Fuller was despatched, caught by Hurst without scoring.
Ravi Patel (31) and James Harris provided the platform for Middlesex to regroup, adding 55 for the eighth wicket, with Patel departing, caught by Hurst off the bowling of George Harding.
Harris ended the day unbeaten on 51, from 104 balls, with eight fours, in partnership with Arthur Godsal (six not out), with Middlesex facing a huge task to turn around their fortunes.
Even if the visitors manage to force a draw in the four-day match, which continues until Friday, Durham look certain to win by virtue of the higher first innings score.