Japanese forward Aoba Fujino was the star of the encounter, scoring twice as City recovered from an early setback to secure all three points at the U-Power Stadium.
The hosts took the lead in the 24th minute through Elisa Bartoli, who headed home to put Inter ahead despite City's promising start.
However, the visitors responded nine minutes later when Laura Blindkilde Brown delivered an excellent pass to Fujino, who finished confidently to make it 1-1.
Fujino struck again in the 44th minute, capitalising on a rebound from Mary Fowler's effort to give Manchester City a 2-1 advantage going into half-time.
Casparij and Clinton complete City's victory
Manchester City continued their attacking dominance after the restart, with captain Kerstin Casparij extending their lead in the 56th minute.
The defender finished a well-worked attacking move involving Sam Coffey to make it 3-1 and put the visitors in a commanding position.
Substitute Grace Clinton completed the scoring in the 70th minute, converting Lauren Hemp's delivery at the far post to seal an emphatic victory.
City's attacking performance was particularly impressive, with all four goals coming from flowing team moves.
Important victory for Manchester City
The result was Manchester City's first win in the league phase after opening their European campaign with three consecutive draws.
The victory moved Andrée Jeglertz's side to seventh position in the 18-team standings with six points, keeping their hopes of securing a top-four finish alive.
Inter, meanwhile, remained on four points after suffering their second defeat of the campaign.
City will now turn their attention to a crucial Women's Super League encounter against Chelsea on Saturday, 14 November, before returning to European action against BK Häcken.
Full-time: Inter Milan Women 1-4 Manchester City Women
Competition: UEFA Women's Champions League, 2026/27 league phase
Venue: U-Power Stadium, Monza, Italy
Manchester City scorers: Aoba Fujino 33', 44'; Kerstin Casparij 56'; Grace Clinton 70'.
Inter scorer: Elisa Bartoli 24'.