Openers Mark Stoneman (46) and Keaton Jennings put on 74 for Durham, but that was as good as it got for the visitors at Lord's as spinner Ollie Rayner took 4-17 to help bowl them out for 204.
Middlesex captain James Franklin also chipped in with 3-26.
The hosts closed on 100-1, trailing by 104, with Nick Gubbins unbeaten on 42 and Nick Compton 10 not out.
County Championship leaders Middlesex enjoyed a fine opening day with bat and ball to take control against Durham.