On the eve of Zimbabwe's first election since his ouster in a de facto coup, the 94-year-old said he hoped his former allies in the "military government" would be voted out of power.
Long lines formed at Zimbabwe polling stations on Monday as the first presidential election not involving former leader Robert Mugabwe began.
"I can't vote for Zanu-PF, I can't vote for the people who have brought me into this state", Mugabe said during a press conference in the garden of his home in Harare on Sunday.
"I think it fairly risky and fairly obvious, that the U.S. are going to have some form of influence", he said. "Americans are playing quite a unsafe game with this, because if the wrong candidate as far as they are concerned, which is Mnangagwa, retains power, if he is able to succeed - and it does look like he is going to - then America will certainly be left on the outside of it".
"This country is enjoying democratic space which has never been experienced before", Mnangagwa said after casting his vote.
Mnangagwa, 75, has has promised change and is the clear front-runner benefitting from tacit military support, loyal state media and ruling party controls of government resources.
"I can't vote for those who have caused me to be in this situation, so there is Chamisa left".
The election victor faces the task of putting Zimbabwe back on track after 37 years of Mugabe rule tainted by corruption, mismanagement and diplomatic isolation that caused a crisis in a country that once had one of Africa's most promising economies.
In a surprise address to the nation after months of silence, Zimbabwe's former leader Robert Mugabe emerged just hours before Monday's historic election declaring that "I will not vote for those who have illegally taken power" and turning his back on the ruling party he long controlled. "He is a citizen".
The run-up to Monday's vote was largely peaceful compared to past elections under Mugabe, where the ruling party and war veterans were accused of violence against opponents. Chamisa's Movement for Democratic Change (MDC) has complained about a flawed voters' roll and opaque ballot paper printing.
But the regional body - the Southern Africa Development Community (SADC) - said it was satisfied with the vote.
His main rival Chamisa is 40 and, if elected, would become Zimbabwe's youngest-ever president.
Mnangagwa, known as "the crocodile", an animal famed in Zimbabwean lore for its stealth and ruthlessness, was removed as vice president by Mugabe last November to make way for his wife, Grace, to seize power, analysts say.
As such, President Mnangagwa said, the world was free to come and witness democracy being practised at its highest level during Zimbabwe's harmonised polls.
"We will win this election to the extent it's free and fair.it's a done deal", he told the BBC.
Chamisa has vowed not to boycott the vote, saying his party would still win despite accusing Mnangagwa and the Zimbabwe Electoral Commission (ZEC) of trying to fix the result.
Mr Mnangagwa is favourite although the latest opinion poll said the race was too close to call.
The results of the presidential elections are due by August 4.
A runoff election is scheduled for September 8 if no candidate receives more than 50 percent of the vote.