Although PNE had tasted success in the FA Cup, it was their only win against Boro in 17 games from 1972 all the way through to 2019.
In the end, a 2-1 win at the Riverside gave the Lilwyhites, then playing in green, the win for boss Alex Neil.
Ashley Fletcher opened the scoring for the home side before a Paul Gallagher free kick levelled things up. Daniel Ayala was sent off just after the hour with Jayden Stockley scoring a header with just nine minutes to go to seal all three points.
1. DJ chases Hugill
Middlesbrough's Jordan Hugill shields the ball from Preston North End's Daniel Johnson. Photo: CameraSport - Alex Dodd
2. Gally scores
Preston North End's Paul Gallagher scores his side's equalising goal to make the score 1-1. Photo: CameraSport - Alex Dodd
3. Trio celebrate
Preston North End's Ben Pearson celebrates with Daniel Johnson after the match with Lukas Nmecha. Photo: CameraSport - Alex Dodd
4. Gally and Rudd celebrate
Preston North End's Paul Gallagher and Declan Rudd celebrates after the match. Photo: CameraSport - Alex Dodd