The actor has earned a reputation as a darling of several of the region's top leftist leaders. He's visited places there rarely seen by Hollywood stars, making comments along the way that drew compliments and criticism.
Now Penn is in the spotlight again, as some slam his Rolling Stone interview with Guzman as overly sympathetic toward the notorious crime boss and others praise him for nabbing a story journalists weren't able to get.
Here's a look at some of the actor's other forays into the world of Latin American policies and politics:
Penn traveled to South America a number of times to meet with Hugo Chavez and was often praised in remarks by the Venezuelan President.
After Chavez's death in 2013, Penn released a statement that showed how close he'd gotten to the Venezuelan leader.
"Today the people of the United States lost a friend it never knew it had. And poor people around the world lost a champion," he said. "I lost a friend I was blessed to have."
He interviewed Cuban President Raul Castro
Even with warming relations between the United States and Cuba, interviews with the country's leaders are rare. But Penn interviewed President Raul Castro in 2008
, publishing an account of the conversation in The Nation that was billed as Castro's first interview with an international journalist.
In the interview, Castro told Penn he'd be willing to meet with Barack Obama if he won the U.S. presidency.
Several years earlier, Penn also met with longtime leader Fidel Castro. It's a conversation he's said deepened his "growing interest in Latin American history."
He may have helped U.S. businessman escape Bolivia
Call him a favorite of the Latin American left if you will, but not all of the region's left-wing leaders are fans of Penn.
The actor ran afoul of Bolivia's government and President Evo Morales as he pushed for the release of Jacob Ostreicher, a flooring contractor from New York who'd been imprisoned there on suspicion of money laundering tied to a rice-growing operation. Ostreicher denied the accusations and claimed that corrupt officials had trumped up the case.
In 2013, Penn testified before a U.S. House Foreign Affairs subcommittee, describing "feces-filled cells" in Bolivian prisons as he asked U.S. lawmakers to pressure sponsors of the Dakar Rally to cancel its planned 2014 route through Bolivia if Ostreicher was not freed.
His comments drew the ire of Bolivian Culture Minister Pablo Groux.
"The remarks by Mr. Penn are his worst acting in all of his career," the culture minister said, according to the state-run ABI news agency.
Later that year, Ostreicher was whisked back to the United States. As the U.S. government denied involvement in Ostreicher's return, rumors swirled that Penn had something to do with it.
He's a tireless advocate pushing for help for Haiti
Penn arrived in Haiti a week after a devastating earthquake struck the island in 2010. He stayed for months, starting an aid organization
there and helping with relief efforts.
Haiti and its people captivated him, he told CNN in 2011
"I think there's also something that happens to you when you land only an hour and a half after you take off from Miami, Florida. And in that much time, you're in a country surrounded by people who have had absolutely no experience or dependence on comfort in their entire experience. ... This is a culture of people who, every time a child's fever rises, has to just wait and see if they're going to die," he said. "And they've persevered through these kinds of basic hardships with so much strength."
He criticized Prince William's Falkland deployment
As Argentina and the United Nations squared off over the territory, which Argentina calls Las Malvinas, Penn seemed to take the South American country's side.
He reportedly described Prince William's 2012 deployment there
on a military mission as "unthinkable."
And on a visit to South America, he called the islands the Malvinas, which sparked criticism of the actor on the other side of the Atlantic.
"I would be happy to call it the Falkland Islands when I'm in England. ... I was with my Argentinean friends at that time," he told CNN in 2012.
If he returns to Argentina, Penn said he'd call the islands the Malvinas again.
"I'm not precious on those things," he said
. "If others are offended by that, I make no apology."
He joked about a Mexican director's green card
After he presented Mexican director Alejandro Gonzalez Iñarritu with the best picture award for "Birdman" at the Oscars last year, Penn's off-the-cuff comment sparked controversy.
"Who gave this son of a bitch his green card?" Penn said before announcing the film's win.
The director brushed off the remark, telling reporters afterward that he found it hilarious.
"Sean and I have that kind of brutal (relationship) where only true friendship can survive," he said.
But on social media, a lot of people weren't laughing
, and the comment caught flack in headlines throughout Latin America.