Addressing the high-level debate at the General Assembly, Guterres said millions of people are living in dread as a result of North Korea's provocative nuclear and missile tests.
"The use of nuclear weapons should be unthinkable," Guterres told the 193-nation assembly meeting in New York.
"But today global anxieties about nuclear weapons are at the highest level since the end of the Cold War."
The fear of nuclear warfare "is not abstract," he added. "Millions of people live under a shadow of dread cast by the provocative nuclear and missile tests" carried out by Pyongyang.
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But China and Russia have warned that US talk of military options to address the North Korean crisis would have a catastrophic result and are pushing for diplomatic talks.
US President Donald Trump, who has threatened North Korea with "fire and fury" unless it changes course, will be in the spotlight on Tuesday when he delivers his maiden address.
Guterres warned that rising tensions were increasing the chance of miscalculation and that "fiery talk can lead to fatal misunderstandings."
"We must not sleepwalk our way into war," he said.
Guterres again called on Myanmar to halt its military campaign against Rohingya Muslims, just hours after Aung San Suu Kyi delivered a nationwide address that failed to quell an international outcry.
More than 420,000 Rohingya have been forced to flee violence in Myanmar's northern Rakhine state in what the United Nations has described as "ethnic cleansing."
"We are all shocked by the dramatic escalation of sectarian tensions in Myanmar's Rakhine state," said Guterres.
"The authorities in Myanmar must end the military operations, and allow unhindered humanitarian access. They must also address the grievances of the Rohingya, whose status has been left unresolved for far too long."
Guterres also spoke out in favour of the Paris agreement on climate change, saying extreme weather events like Hurricane Irma are becoming "the new normal of a warming world.