Mauricio Pochettino's side made a fine start to the new campaign, but have lost their last two in the league to Watford and Liverpool, and there is already pressure on the team to deliver a result at the San Siro.
Inter are back in the competition for the first time since the 2011-12 campaign, and it will be the fifth time that these two teams have locked horns, with the pair both posting two wins each.
Barcelona and PSV Eindhoven are also present in Group B, which makes Tuesday's clash in Milan even more important as both Tottenham and Inter look to put an early three points on the board.
Here, Sports Mole looks at how Spurs could line up in Italy.
Out: Hugo Lloris (thigh), Vincent Janssen (foot), Juan Foyth (thigh), Dele Alli (hamstring)
Doubtful: Moussa Sissoko (hamstring)
Tottenham will again be without the services of number one goalkeeper Hugo Lloris due to a thigh problem, which means that Michel Vorm will start between the sticks despite struggling to impress in the defeat to Liverpool at the weekend.
Dele Alli is also still absent with a hamstring problem, but Son Heung-min came off the bench against Liverpool, and the attacker could now be handed a spot in the final third of the field alongside Harry Kane, who will not be rested.
Pochettino went with a back four against Liverpool, but Davinson Sanchez is expected to come into the XI alongside Toby Alderweireld and Jan Vertonghen in central defence, while Ben Davies should replace Danny Rose down the left.