On Friday, the court said the electoral board committed "irregularities and illegalities" during last month's vote, harming the integrity of the election.
The Nairobi-based court ordered another presidential election to be held within 60 days.
"The declaration [of Kenyatta's win] is invalid, null and void," said Judge David Maraga, announcing the verdict of four out of the six judges.
No presidential election in Kenya has ever been nullified before.
Maraga said the election commission "failed, neglected or refused to conduct the presidential election in a manner consistent with the dictates of the constitution".
In a national address following the court decision, Kenyatta said that while he "personally disagrees" with the ruling, he will "respect it, as much as I disagree with it".
"It is important to respect the rule of law ... we are ready to go back again to the people with the same agenda," he said as he appealed for calm.  
But he also criticised the six members of the Supreme Court for going "against the will of the people", by nullifying the vote. 
Later on Friday, Kenyatta told his supporters that his status as "president-elect" had been taken away by "Maraga and his crooks."
He added that the judges should know they are dealing with an incumbent president.
A lawyer for Kenyatta, Ahmednasir Abdullahi, said the decision was "very political" and the election board had "done nothing wrong". But he said the decision had to be respected.
The protest was brought before the Supreme Court by opposition leader Raila Odinga.
Kenyatta was announced the winner with 54 percent of the vote - but Odinga claimed the election was rigged with electronic voting results hacked into and manipulated in favour of Kenyatta.
Kenya's electoral commission had said there was a hacking attempt but it had failed. International election observers said they saw no interference with the vote.
Odinga supporters erupted in jubilation after the decision was announced.
"This is an unprecedented ruling," Odinga said outside the court. "This is a triumph for the people of Kenya."
He condemned members of the electoral board and vowed to press for criminal proceedings.
"We have no faith at all in the electoral commission as currently constituted. They have committed criminal acts," said Odinga.
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