The answer seemingly put him at odds with running mate Donald Trump, who has largely advocated a pullback from foreign conflicts and requiring US allies to take on more of their own defense. It also lines him up more closely with Democratic presidential candidate Hillary Clinton and his debate opponent, Virginia Sen. Tim Kaine, both of whom have advocated a Syrian no-fly zone.
"The United States of America should be prepared to use military force to strike military targets of the Assad regime to prevent them from this humanitarian crisis that is taking place in Aleppo," Pence said in reference to the besieged Syrian city.
"I truly do believe that what America ought to do right now is to immediately establish safe zones," Pence said at the first and only vice presidential debate, at Longwood University in Farmville, Virginia, "so that families and vulnerable families with children can move out of those areas (and) work with our Arab partners in real time to make that happen."
It wasn't the only time Pence departed from his running mate's script on foreign policy issues or denied some of Trump's foreign policy pronouncements.
Pence repeatedly criticized Clinton and Kaine for the drawdown of US troops in Iraq, blaming Clinton for failing to negotiate an agreement with Iraq that would have provided legal protections for US troops there. While the Obama administration was not successful in making such an arrangement, Pence didn't mention that the Obama White House inherited an agreement from President George W. Bush that required all US troops to leave Iraq by 2011 or that the Iraqi parliament had refused to grant US troops legal immunity if they stayed in the country.
Moreover, in a 2006 interview with CNBC, Trump said he wanted to see Bush, then still president, "get us out of Iraq, which is a total mess, a total catastrophe, and it's not going to get any better. It's only going to get worse."
Pence also denied that he or Trump had ever praised Russian President Vladimir Putin as a better leader than President Barack Obama, though both have spoken positively of him and the Indiana governor told CNN's Dana Bash in September that he was a "stronger leader" than the current occupant of the Oval Office.
In Asia, Trump advocated letting US allies deal with the threat of a nuclear North Korea on their own, even suggesting that longtime US partners like South Korea and Japan obtain nuclear weapons themselves. Kaine pounced on this at one point, saying that "Trump believes that the world will be safer if more nations have nuclear weapons."
Pence, for his part, outlined a position that didn't sound much like Trump's. The Indiana governor said that "we need an effective US diplomacy to marshal the nations in the Asian rim to put pressure on North Korea," which is what the Obama administration and its predecessors have favored.
The White House, however, has opposed a no-fly zone in Syria. The safe zone would be an area inside the country that the US and allied planes would defend from Syrian or Russian attack. It raises thorny legal problems, because doing so without the host country's permission means violating international law. And the possibilities for military escalation are very high if a US, Russian or Syrian plane were shot down. At this point, many military experts say a no-fly zone isn't possible.
Trump has said that he would be willing to support a safe zone, but only financially. When asked whether the US should be involved in establishing safe zones, Trump told CBS' "Face the Nation" in October 2015 that he would "help them economically, even though we owe $19 trillion."
In that same interview, Trump said he would "love a safe zone for people."
"What they should do is, the countries should all get together, including the Gulf states, who have nothing but money, they should all get together and they should take a big swath of land in Syria and they do a safe zone for people, where they could to live, and then ultimately go back to their country, go back to where they came from," Trump said.
Clinton called for a no-fly zone in Syria in October 2015, soon after Russia entered the country and started a bombing campaign to help President Bashar al-Assad.
"I personally would be advocating now for a no-fly zone and humanitarian corridors to try to stop the carnage on the ground and from the air," Clinton said in an interview with Boston's WHDH.
The White House has said a Syrian safe zone is off the table because of the enormous military commitment it would take to effectively enforce it and the ongoing responsibility of protecting its borders. Several Pentagon officials have told Congress that the costs would outweigh the benefits because it would increase the risk of a direct confrontation between US forces and Russia or Syria in the skies.
President Barack Obama laid out some of the complexities of a no-fly zone in remarks he made in Germany in April. "It's not a matter of me not wishing I could help and protect a whole bunch of people," Obama said. "It's a very practical issue about how do you do it? And who is going to put on a bunch of ground troops inside of Syria? And how do you let people in? And who do you let in and who do you let out? And how is it monitored?"
Obama said that after multiple talks about a possible safe zone with the Defense Department, "It is very difficult to see how it would operate, short of us essentially being willing to (use) militarily take over a big chunk of that country."
Kaine has said that while he initially supported the administration's argument against safe zones, by December 2015, he had changed his mind. That month he told a Senate Armed Services Committee hearing that "the absence of the humanitarian zone will go down as one of the big mistakes that we've made."