The two men led an expedition to cross Australia south to north to try to find new pasture land and water for Melbourne which had grown rich during the gold rush.
But their journey came to an end in 1861 in outback Queensland after the pair reached the Gulf Of Carpentaria but died of starvation as they trekked back to Melbourne.
Victorian Governor David De Kretser Melbourne Lord Mayor Robert Doyle and historian Dave Phoenix will unveil a new plaque in Royal Park from where the explorers departed in August 1860.
Descendants of Wills' brother Tom, a great great great grand-daughter, will be at the ceremony along with descendants of expedition member William Brahe and Melbourne mayor at the time, Richard Eades.
Burke and Wills died as single men and left no children.
Mr Doyle will read the speech that his counterpart Richard Eades made at the departure while Mr Phoenix, who has walked the track pioneered by the explorers, will read the reply from Burke.
"The Burke and Wills story is a fascinating one that has endured for 150 years," Mr Phoenix said.
"When they departed there were a number of formal farewells in Melbourne - everyone in the colony wanted to say farewell to Burke."
He said 150 years ago on Tuesday the governor went to Royal Park to look at the camels that were part of the expedition and 150 years on Wednesday the men of the expedition went to the Royal Society of Victoria building to sign their contracts.
The 30 minute ceremony was to be held on August 21, the day after the original departure, but those plans were scuppered when Prime Minister Julia Gillard called the federal election for that date.
