The pandemic, increasingly urgent concerns about climate change, disruptions to the economic supply chain and uncertainty over the future of Afghanistan are some of the major topics on the summit agenda and likely to come up in Biden’s other meetings with world leaders.
The G-20 summit in Rome comes just before many of the leaders will participate in the COP26 climate conference starting Monday in Glasgow, Scotland.
Here’s are some key things to watch for:
'America back' or 'America first'?
Biden declared "America is back" when he took office -- a pledge to affirm, with tested and steady leadership, the alliances strained by four years of President Donald Trump.
But the chaotic withdrawal of U.S. troops from Afghanistan and the swift collapse of the country to the Taliban frustrated and stunned some European leaders, who were forced to deal with policy fallout as well as resettling refugees from the war-torn country.
That, together with the Biden administration’s reluctance to ease travel restrictions for foreigners until the fall -- much later than Europe -- has led some allies to wonder whether "America First" didn’t leave the White House with Trump – and whether America can be counted on to keep its military and foreign policy commitments.
"The real question looming large over the summit is, how reliable will the United States be in the coming years? Not just because of the prospect that Trump could return, but where does Biden see America's responsibilities shifting?" Brett Bruen, a former U.S. diplomat, told ABC News.
"There certainly are a lot of people after the withdrawal from Afghanistan that are wondering about their own security," he said.
Plans for the pandemic, supply chain challenges
The G-20 leaders will meet in person for the first time since 2019 as the world is on track to miss the World Health Organization and United Nations’ goal to vaccinate at least 40% of the population in every country by the end of 2021.
The U.S. frustrated world health officials by moving forward with COVID-19 vaccine boosters -- even as experts pushed to first use supplies to vaccinate more people across the developing world. Biden has promised to ship more than 1 billion vaccine doses abroad by next fall -- but a key question is whether leaders will reach any agreement to speed up the production or delivery of vaccines to poorer nations.
White House national security adviser Jake Sullivan on Monday also told reporters that Biden hopes to improve "transparency" and communication between countries around supply chain bottlenecks. Speaking to reporters on Air Force One on Thursday night, Sullivan said Biden would convene a supply chain meeting with other world leaders in Rome.
On the economic front more broadly, the U.S. also wants the G-20 countries to promote new forms of debt relief for emerging economies that have struggled during the pandemic.
The U.S. will also tout the new international agreement on a global corporate minimum tax of 15%, which, if approved by Congress in the United States and lawmakers in the countries party to the deal, would make it more difficult for multinational corporations to avoid paying taxes, potentially raising billions of dollars in revenue.
US and France: Repairing the oldest alliance
The last time they met in Europe, Emmanuel Macron and Joe Biden laughed and clasped hands at the beach in England, huddling for longer than scheduled; the French president declared that America was "definitely" back.
Their meeting on Friday ahead of the G-20 in Rome had a different tone, with Biden expressing regret after the U.S. infuriated its oldest ally by announcing a new security agreement with the United Kingdom and Australia that scuttled a lucrative French military contract to provide a new submarine fleet to Australia.
"I want to get something clear in front of all the press, we view you as an incredible serious valued partner," Biden said at their photo op, grabbing Macron's hand to shake it. "You’ll be there for us, we’ll be there for you, there’s a lot more work we can do together."
"Thank you," Macron replied. "No, no. Don’t thank me. Thank you," Biden said.
When a reporter asked if the relationship is repaired, Biden responded, "What happened uh, was to use an English phrase, what we did was clumsy. It was not done with a lot of grace."
"I was under the impression certain things had happened that hadn’t happened. And uh, but uh, I want to make it clear. France is an extremely, extremely valued partner. Extremely. And a power in itself. And so, I don’t know any reason -- we have the same value system," Biden said.
White House wranglers attempted to shout pool reporters out of the room, but Macron ultimately got to weigh in.
"We are clarifying together what we have to clarify," he said. "And now what’s important is precisely to be sure that such a situation will not be possible in the future. It’s time for coordination, it’s time to have cooperation."
Several senior Biden administration officials have met with him in Paris, and Vice President Kamala Harris will travel to Paris next month.
Separately, Biden could meet with other world leaders on the sidelines of both conferences. Sullivan on Thursday night confirmed that Biden is expected to meet with Turkish President Recep Tayyip Erdogan in Scotland and will hold a meeting with the leaders of the United Kingdom, France and Germany in Rome on the status of negotiations over Iran's nuclear program.
'Build Back Better' or 'blah, blah, blah'?
The White House had hoped to broker a major social policy deal with congressional Democrats before Biden left for Europe Thursday -- and with it, new U.S. commitments to fight climate change. But having failed to do so, how will Biden sell any potential progress abroad when his party failed this week to pass a package that included $550 billion in clean energy and climate investments? A figure that experts say is insufficient to meet the Paris climate agreement commitment to reduce 2005 emissions levels by 50% by 2030.
Or, as activist Greta Thunberg -- who will be in Scotland -- put in remarks in September, will experts and activists see Biden's "Build Back Better" plan as more "blah blah blah"?
John Larson, a director of power and energy research at the Rhodium Group, told ABC News that the still-developing Democratic climate plan "could be the single largest action by Congress, if not the federal government, to reduce greenhouse gas emissions ever."
If an agreement is eventually cemented in Washington, its terms could eventually give Biden more credibility to extract greater climate commitments from like-minded G-20 leaders, Matthew Goodman, a senior vice president for economics at the Center for Strategic and International Studies, said on a call with reporters ahead of the president's trip.
Chinese, Russian leaders to skip attending in person
China's President Xi Jinping will be participating in the G-20 summit virtually and will not attend the COP26 climate conference in Scotland. It’s a blow to the ambitions of the U.S. and other nations seeking to curb emissions given that China is the largest carbon emitter and home to half of the coal-fired power plants in the world.
At a time when some experts worry that Chinese military tests could prompt a new Cold War-style arms race, could the in-person meetings Biden has in Europe on the sidelines of the summits help align the U.S. and its allies against what the Biden administration has called "the biggest geopolitical test of the 21st century?"
Bruen, the former diplomat and Obama administration official, called Xi Jinping’s absence a "strategic mistake" that would work in Biden’s favor.
"The one thing that Joe Biden can do better than almost any other modern American president is to charm the socks off of even his deepest skeptics," he said. "I would see this this as a moment for Biden to really try and use the powers of personal charm to advance what he wants when it comes to getting our fellow allies, and those that care about these issues, to do more than just say in private that they're concerned."
Another notable in-person absence: Russian President Vladimir Putin.