Under his low-key direction, the United Arab Emirates has put a man into space, sent a probe to Mars and opened its first nuclear reactor, while using its oil-funded clout to develop a more assertive foreign policy.
Closely allied with Saudi Arabia, it has emerged as a leader of a reshaped Middle East since the retreat of traditional Arab powers and the reduced involvement of the United States, forging ties with Israel and joining a war against Iran-backed militants in Yemen.
Russian President Vladimir Putin was quick to offer his congratulations, saying his election would "help reinforce the friendly relations" between the two countries.
Official media had already named Sheikh Mohamed as the ruler of Abu Dhabi, the UAE's richest emirate, on Friday, inheriting one of the main titles held by Sheikh Khalifa who died at 73.
'Running the show'
Sheikh Mohamed, wearing a light grey kandura or robe, was a pall-bearer at the funeral prayers for Sheikh Khalifa who was laid to rest in Abu Dhabi's Al Bateen Cemetery just hours after his death was announced, in accordance with Muslim tradition.
Flags are at half-mast around the UAE and businesses and government offices are closed for three days as the country enters a 40-day period of mourning for Sheikh Khalifa, who had ruled since 2004.
Sheikh Khalifa's death drew condolences from world leaders, including US President Joe Biden, Britain's Queen Elizabeth, Israel's prime minister Naftali Bennett and Iran, demonstrating the UAE's diverse allegiances.
France's president Emmanuel Macron is to travel to Abu Dhabi on Sunday to pay tribute to the late Emirati leader and show support for the new president, his office announced. Egyptian president Abdel Fattah al-Sisi is also headed to the UAE, along with Sudan's de facto leader Abdel Fattah al-Burhan.
Neighbouring Saudi Arabia has put sports and entertainments on hold and several countries have announced periods of mourning.
Sheikh Mohamed, who was named crown prince of Abu Dhabi in November 2004, is the third son of Sheikh Zayed bin Sultan Al Nahayan -- the revered founder of the UAE.
He has been serving as deputy commander of the armed forces and chairman of the Executive Council of Abu Dhabi, which controls the substantial finances of the emirate which sits on 90 percent of the country's oil production.
The UAE, a former British protectorate, has gone from desert outpost to booming state in its short history, fuelled by its oil wealth and Dubai's rise as a trading and financial centre.
Sheikh Mohamed took a prominent role after Sheikh Khalifa retreated from public view in 2014, when he had surgery after a stroke. The cause of his death was not announced.
The new president is likely to face greater competition to UAE's status as the regional financial hub, particularly from Saudi Arabia, and may toughen its stance on Iran, analysts say.
But "functionally it changes little; MBZ has been running the show almost from the get go", tweeted Ryan Bohl, a Middle East analyst at Stratfor Worldview.