More than 16 miles (27 km) of roads in central London will be closed on Sunday as part of Car Free Day.
Streets will be shut around Tower Bridge, London Bridge and the City of London for the Reimagine event.
A festival space on Bank junction, a hedge maze in Cheapside and a sunrise yoga session on Tower Bridge will replace the usual traffic.
Sadiq Khan said he hoped the event “will inspire people to walk and cycle as part of their daily routine”.
The mayor of London has previously said he wants 80% of all journeys in the capital to be made by walking, cycling or using public transport by 2041, compared to 63% today.
Organisers hope more than 150,000 people will join the events, which will also see car parking spaces turned into “parklets” where people can play games, do gardening or relax while listening to music.
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Road closures and restrictions are set to be enforced in the Square Mile and parts of Southwark and Tower Hamlets between 07:00 and 19:00 BST.
London and Tower bridges will both be closed to general traffic for the same time period, although buses and emergency vehicles will still be able to cross London Bridge.