During a solemn ceremony at the General Assembly, the former prime minister of Portugal placed a hand on the UN charter and took the oath of office administered by the president of the General Assembly, Peter Thomson.
The first former head of government at the UN helm, Guterres takes over from Ban Ki-moon on January 1 amid ongoing bloodshed in Syria and questions over how the US role in the world chould shift under President-elect Donald Trump.
"This organization is the cornerstone of multilateralism, and has contributed to decades of relative peace, but the challenges are now surpassing our ability to respond," Guterres said in an address.
"The UN must be ready to change."
The 67-year-old socialist politician said the United Nations must "recognize its shortcomings and reform the way it works," singling out the failure to prevent crisis as a serious weakness.
The UN's refugee chief for a decade, Guterres was sworn in as Syrian forces were on the verge of retaking the entire city of Aleppo -- a potential turning point in the nearly six-year war.
"This is a war in which everybody is losing. This became a threat for everybody around the world," Guterres later told journalists. "It is high time to put an end to this nonsense."
Guterres vowed to "engage personally" in conflict resolution, signalling a more pro-active approach to the role of secretary-general than under the 72-year-old Ban, the South Korean who led the world body for two five-year terms.
The election of Guterres has energized UN diplomats who see him as a skilled politician, able to overcome divisions that have crippled the United Nations, notably over Syria.
But Trump's shock election has raised questions over Washington's future role in the world and its relationship with the United Nations -- as the world body's biggest financial backer.
The new UN chief will begin work just weeks before Trump takes office on January 20.
"Fear is driving the decisions of many people around the world," Guterres said, in a reference to the surge of populism that propelled Trump to the White House.
Citizens worldwide are losing confidence in their governments and in global institutions, he said, adding that it was "time to reconstruct relations between people and leaders."
He pledged to show the new US administration a "clear will to cooperate in relation to the enormous challenges we will be facing together."
Guterres laid out three priorities for change during his five-year term: work for peace, support sustainable development and improve internal UN management.
The 71-year-old United Nations has been criticized for its clunky bureaucracy, which has at times slowed down the response to global emergencies.
Guterres vowed to press ahead with gender parity at the United Nations, saying it was a priority to appoint more women to senior posts.
An engineer by training and a practicing Catholic, Guterres fought for migrants' rights as UN High Commissioner for Refugees from June 2005 to December 2015.
He served as prime minister of Portugal from 1995 to 2002, anchoring his country to the European Union and working to raise living standards.
US Ambassador Samantha Power praised Guterres as "the man for the job in such challenging times."