Tottenham's manager has won 13 of his 14 FA Cup matches against lower-league opposition, though, and the Portuguese will be expecting a response from his players at the Riverside Stadium.
That said, Boro will enter the match off the back of four straight wins in the Championship.
Here, Sports Mole looks at how the visitors could line up this weekend.
Tottenham will be without a number of key players this weekend, with Harry Kane and Tanguy Ndombele joining Ben Davies, Hugo Lloris and Danny Rose on the sidelines.
Spurs confirmed on Friday that leading scorer Kane had picked up a hamstring injury against Southampton, and the England captain is now facing a period on the sidelines.
Eric Dier and Kyle Walker-Peters are both pushing to be involved against Jonathan Woodgate's side, though, having overcome illness and injury respectively.
Key attacker Son Heung-min is also available following suspension, and Mourinho is expected to send a strong XI onto the field due to the form of their opponents this weekend.
That said, changes from the defeat at St Mary's are likely due to the gruelling fixture list, with Michel Vorm, Giovani Lo Celso, Erik Lamela, Harry Winks and Juan Foyth all pushing for spots in the XI.