Working behind the scenes for years as de facto leader, Sheikh Mohammed, 61, transformed the UAE military into a high-tech force, which coupled with its oil wealth and business hub status, extended Emirati influence internationally.
Mohammed began wielding power in a period when his half-brother President Sheikh Khalifa bin Zayed, who died on Friday, suffered bouts of illness, including a stroke in 2014.
MbZ, as he is known, was driven by a "certain fatalistic line of thinking" that Gulf Arab rulers could no longer rely on their main supporter the United States, according to former US envoy to the UAE Barbara Leaf, especially after Washington abandoned Egypt's Hosni Mubarak during the 2011 Arab Spring.
From his power base in the capital Abu Dhabi, Sheikh Mohammed issued a "calm and cold" warning to then-President Barack Obama not to back uprisings that could spread and endanger Gulf dynastic rule, according to Obama's memoir, which described MbZ as the "savviest" Gulf leader.
A US State Department official serving in the Biden administration, which has had fraught ties with the UAE in recent months, described him as a strategist who brings historical perspective to discussions.
"He will talk not only about the present, but go back years, decades, in some cases, speaking to trends over time," the official said.
MbZ backed the 2013 military ousting of Egypt's elected Muslim Brotherhood president Mohammed Mursi, and championed Saudi Arabia's Prince Mohammed bin Salman as he rose to power in a 2017 palace coup, touting him as a man Washington could deal with and the only one able to open up the kingdom.
Encouraged by warm ties with the then US President Donald Trump, the two Gulf hawks lobbied for Washington's maximum pressure campaign on Iran, boycotted neighbouring Qatar for supporting the Muslim Brotherhood, and launched a costly war to try to break the grip of Yemen's Iran-aligned Houthis.
The UAE also waded into conflicts from Somalia to Libya and Sudan before upending decades of Arab consensus by forging ties with Israel in 2020, along with Bahrain, in US-brokered deals known as the Abraham Accords that drew Palestinian ire.
The accords were driven by shared concerns over Iran but also perceived benefits to the UAE economy and fatigue with a Palestinian leadership "that doesn't listen", said one diplomat.
While diplomats and analysts see the alliance with Riyadh and Washington as a pillar of UAE strategy, MbZ has not hesitated to move independently when interests or economic reasons dictate.
The Ukraine crisis exposed strains with Washington when the UAE abstained from a U.N. Security Council vote condemning Russia's invasion. As an OPEC producer, along with oil titan Riyadh, the UAE also rebuffed Western calls to pump more.
Abu Dhabi has ignored other US concerns by arming and backing Libya's Khalifa Hafter against the internationally recognised government and engaging with Syria's Bashar al-Assad.
With Riyadh, the biggest divergence came when the UAE largely withdrew from Yemen as the unpopular war, in which more than 100 Emiratis died, got mired in military stalemate.
When Sudan's President Omar Hassan al-Bashir reneged on a promise to abandon Islamist allies, Abu Dhabi orchestrated the 2019 coup against him.
Although he says he was attracted to their Islamist ideology in his youth, MbZ has framed the Muslim Brotherhood as one of the gravest threats to stability in the Middle East.
Like Saudi Arabia, the UAE accuses the Brotherhood of betrayal after it sheltered members persecuted in Egypt in the 1960s, only to see them work for change in their host countries.
"I am an Arab, I am a Muslim, and I pray. And in the 1970s and early 1980s I was one of them. I believe these guys have an agenda," MbZ said in a 2007 meeting with US officials, according to Wikileaks.
Educated in the UAE and the military officer's college at Sandhurst in Britain, Sheikh Mohammed's mistrust of Islamists heightened after 2001, when two of his countrymen were among the 19 hijackers in the Sept 11 attacks on the United States.
"He looked around and saw that many of the younger generation in the region were very attracted to Osama bin Laden's anti-Western mantra," another diplomat said. "As he once said to me: 'If they can do it to you, they can do it to us.'"
Despite years of enmity, MbZ chose to engage with Iran and Turkey as COVID-19 and rising economic competition with Saudi Arabia turned focus to development, pushing the UAE towards further liberalisation while keeping a lid on political dissent.
Seen as a moderniser at home and a charismatic people's man by many diplomats, MbZ doggedly promoted the previously low-profile Abu Dhabi, which holds the UAE's oil wealth, by spurring development in energy, infrastructure and technology.
As deputy supreme commander of armed forces he was credited with turning the UAE military into one of the most effective in the Arab world, according to experts who say he instituted military service to instil nationalism rather than entitlement among an affluent population.
"He doesn't beat around the bush ... he wants to know what isn't working well, not just what's working," said a source with access to Sheikh Mohammed.