Asked about the US presidential election on his flight back to Rome from Singapore, the Pope said not welcoming migrants is a "grave" sin and likened having an abortion to an "assassination".
He said US Catholics would have to "choose the lesser evil" when they vote in November, without elaborating.
Francis was speaking in a press conference with journalists after a 12-day tour across Southeast Asia and Oceania.
Although the pontiff did not use Trump and Harris' names, he referred specifically to their policies and their genders.
Despite criticising both candidates, he said Catholics should vote.
"Not voting is ugly," the 87-year-old pontiff said.
"It is not good. You must vote."
"You must choose the lesser evil," he said.
"Who is the lesser evil? That lady, or that gentleman? I don't know. Everyone, in conscience, (has to) think and do this."
Catholics, numbering about 52 million across the United States, are often seen as crucial swing voters.
In some battleground states, including Pennsylvania and Wisconsin, more than 20 per cent of adults are Catholic.
Francis said both candidates' policies are "against life".
"Whether it is the one who is chasing away migrants or the one that (supports) killing babies," the Pope said.
The Pope has made the plight of migrants a priority of his pontificate and speaks out emphatically and frequently about it.
While strongly upholding church teaching forbidding abortion, the pontiff has not emphasised church doctrine as much as his predecessors.
The Pope said migration is a right described in Scripture, and that anyone who does not follow the biblical call to welcome the stranger is committing a "grave sin".
He was also blunt in speaking about abortion.
"To have an abortion is to kill a human being. You may like the word or not, but it's killing," he said.
"We have to see this clearly."
Trump pledges massive deportations, just as he did in his first White House bid, when there was a vast gulf between his ambitions and the legal, fiscal and political realities of such an undertaking.
The US bishops conference, for its part, has called abortion the "pre-eminent priority" for Catholics in the country in its published voter advice.
Harris has strongly defended abortion rights and has emphasised support for reinstating a federal right to abortion.
with AP
