On 22 June 2020, Kyah Simon departed Melbourne City through a mutual contract termination in pursuing overseas opportunities.

On 2 July 2020, captain Steph Catley had departed the club for Women's Super League side Arsenal.

The full draw for the 2020–21 W-League was released on 30 November 2020;[2] the first match to be kicked off exactly a month later on 30 December away to Sydney FC in a double-header at ANZ Stadium.

[5] A friendly against the Melbourne Victory was played on 19 December 2020 in preparations for the upcoming W-League campaign, resulting in a 3–3 draw via goals by Franny Iermano, Tori Tumeth and Rhali Dobson.

[6] On 20 December 2020, City signed Japanese international attacker Chinatsu Kira from Urawa Reds, and re-signed defender Emma Checker the next day.

[7] A further four rounds for City were confirmed two days later, their away match to Canberra United brought forward due to travel restrictions and border closures based on the COVID-19 pandemic in the Australian Capital Territory,[8] back-to-back home fixtures at Frank Holohan Reserve against Melbourne Victory and Adelaide United in the space of four days, and an away match to Perth Glory.

[10] Four players were unavailable for Round 2's clash against Canberra United; Chelsea Blissett and Sofia Sakalis with torn ACLs, Alex Chidiac quarantined and Emma Checker in stress fracture.

[11] City would then play their first loss of the season on 3 January, going down 2–1 to Canberra through a late winner, dropping from third to sixth place spot.

With the chance for redemption against the Victory the next week after the heavy defeat, City won the away derby 3–2 to record their first win of the season and move them back up a spot to sixth place.

[19] City lost to Adelaide 2–1; with a consolation goal for Checker but still falling short and dropping again to seventh place.

[22] City finished their first two months of the campaign with just one win, one draw and four losses; four points total in the first six matches.

[23] Margot Robbine was another new promotion and Samantha Johnson out due to injury for City's squad to face Sydney on 4 February.

[35] Micah prior to the match was out due to knee injury, meaning Barbieri was to start and play her first game for City since 2017.

[36] With just three days time until City's next match at home against Newcastle, the club signed Sophia Varley on 13 March following Micah's knee injury.

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