Street artist Akse P19 painted the artwork in tribute to the 100-year-old, who died on 2 February after contracting coronavirus.
The Army veteran won the nation's hearts by walking 100 laps of his garden during the first lockdown, raising almost £33m for NHS charities.
The mural has been painted on the corner of Tib Street and Thomas Street in the city's Northern Quarter.
Akse P19 is the artist behind a number of murals in the city including a tribute to NHS workers and George Floyd, who died after being arrested in the US in May.
The street artist also created a mural to footballer Marcus Rashford in Withington in recognition of the Manchester United star's successful campaign to extend free school meals.
Capt Sir Tom walked 100 laps of his garden in Marston Moretaine, Bedfordshire, during the first lockdown last year.
He had initially set out to raise £1,000 for NHS Charities Together by walking 25m (82ft) loops of his garden, but eventually raised £32,794,701 from more than 1.5 million supporters.
The Army veteran was knighted by the Queen in July in a special ceremony at Windsor Castle.