Louis Botha Ave, which is part of the M11 metropolitan route, begins at the top of the Johannesburg CBD in the suburbs of Hillbrow and Berea at the Clarendon Place and Willie Street junction and then heads north-east passing between Houghton to the north and Yeoville and Bellevue to the south.

Midway through Orange Grove, the road bends northwards and passes through Orchards and Sydenham and the smaller suburbs of Maryvale, Forbesdale, Cheltondale, Rouxville and Hawkins Estate.

[1]: 57  The road crosses Corlett Drive in Bramley before ending a short distance later at the Artwright Avenue (M40) junction in the light industrial suburb of Wynberg with the old township of Alexandra to the east.

[5]: 39 A largely business street, there are some problems on Louis Botha Avenue, including urban decay caused by illegal land uses, such as shebeens.

[6] In 2014, construction began on the expansion of Johannesburg's Rea Vaya bus rapid transit system to Louis Botha Avenue.