Guterres told a Holocaust commemoration event that discrimination faced by immigrants and refugees as well as the stereotyping of Muslims were opening the door to even more extreme hatred.
His remarks came as US President Donald Trump was reportedly preparing to suspend the US refugee program and halt visas for travellers from seven Muslim countries.
"I am extremely concerned at the discrimination faced by immigrants, refugees and minorities across the world. Today, I find the stereotyping of Muslims deeply troubling," he told the General Assembly.
"We need to be vigilant," Guterres added.
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"The United Nations itself must do more to strengthen its human rights machinery, and to push for justice for the perpetrators of grave crimes."
Trump is reportedly considering a draft executive order that would ban refugees from Syria from entering the United States while the broader US refugee program would be suspended for 120 days.
"The world is a mess. The world is as angry as it gets. What, you think this is going to cause a little more anger? The world is an angry place," Trump told ABC News this week about his plan.
Guterres said anti-Semitism, racism, xenophobia and anti-Muslim hatred were being whipped up by populism and "by political figures who exploit fear to win votes.