Biden said that one of his priorities was discussing "the plague of fentanyl, which has killed 100,000 Americans so far," referring to the often-deadly opioid smuggled across the border by Mexican drug cartels.
Another vital issue was "how we can tackle irregular migration, which I think we're well on our way to doing," he said at the start of the talks, calling Mexico a "true partner."
While Lopez Obrador gave Biden a warm welcome on his arrival at the presidential palace, his tone hardened at the formal talks, where the Mexican leader appealed for a change in US attitudes toward the region.
"It is time to end this oblivion, this abandonment, this disdain for Latin America and the Caribbean," Lopez Obrador said.
Biden defended Washington's record, saying it had spent "tens of billions of dollars" in the past 15 years alone that had benefited the region.
"The United States provides more foreign aid than every other country just about combined," he said.
"Unfortunately, our responsibility just doesn't end in the Western Hemisphere," Biden added.
Lopez Obrador and his wife Beatriz Gutierrez greeted the US president and Jill Biden at the National Palace for a welcome ceremony notable for its smiles, enthusiastic handshakes and even hugs.
The first wives delivered a joint message in English and Spanish emphasizing the two countries' shared values.
"We believe that freedom of faith, speech and the press is the foundation of democracy, and that the voice of the people is powerful," Jill Biden said.
"We reject all forms of xenophobia, racism, discrimination and classism, and dare to dream of a time where all are equal and free," she said.
In 2021, the United States and Mexico announced a revamp of their fight against drug trafficking to address the root causes of migration, encourage economic development and bolster curbs against cross-border arms smuggling.
Mexico is plagued by cartel-related bloodshed that has seen more than 340,000 people murdered since the government deployed the military in the war on drugs in 2006.
Days before Biden's visit, Mexican security forces captured a son of notorious drug kingpin Joaquin "El Chapo" Guzman, who is serving a life sentence at a US prison.
Climate change and cooperation in clean energy technologies will also be on the summit agenda, with Mexico hoping to benefit from Washington's efforts to reduce its reliance on Asia-based manufacturers.
On his way to Mexico, Biden made a politically charged visit to the southern US border for the first time as president.
He stopped for several hours in the border city of El Paso, Texas, meeting with US officials and inspecting a section of the tall fencing that snakes along the frontier.
"They need a lot of resources. We're going to get it for them," Biden told reporters after his visit to a customs post.