Speaking to viewers from his kitchen, Hanks, who recently recovered from the coronavirus, delivered the opening monologue dressed in a suit. He joked that it was the first time he'd worn anything but sweatpants for a month.
"Hey all you cool cats and kittens," Hanks greeted his virtual audience with a reference to "Tiger King," the popular Netflix documentary series. "It's good to be here, though it is also very weird to be here hosting 'Saturday Night Live' from home."
Hanks went on to joke that ever since his coronavirus diagnosis, he's been like "America's dad ... No one wants to be around me very long, and I make people uncomfortable."
He added that he and his wife, Rita Wilson, who also tested positive, are now doing well.
The Oscar winner first revealed his condition on March 11, when he was in Australia working on a film about Elvis Presley. The world paid close attention as Hanks, 63, tweeted updates on his condition and urged people to shelter in place to reduce spread of the virus. He and Wilson returned home to California in late March after two weeks in quarantine.
"This 'Saturday Night Live' is going to be a little different," Hanks warned, standing in his kitchen.
"For one thing, it is being filmed entirely by the 'SNL' cast who are quarantined in their homes just like this. Well, not like this," he quipped, referencing his upscale digs. "Also, there's no such thing as Saturdays anymore. It's just every day is today."
He continued: "And we're not really live, but we are doing everything we can to make this feel like the 'SNL' you know and love. I am even using cue cards, see?"
Then he presented a cue card that read, "I am even using cue cards."
The monologue did include some familiar lines, too.
"We have a great show for you tonight," Hanks said. "Now, is it going to look a little different than what you're used to? Yes. Will it be weird to see sketches without big sets and costumes? Sure. Will it make you laugh? Eh. It's 'SNL.' There will be some good stuff, maybe one or two stinkers. You know the drill."
The episode had a distinctly homemade vibe with cast members using simple props and makeshift costumes. Kate McKinnon brought back her Ruth Bader Ginsburg impression, which included RBG's home workout routine.
Later, McKinnon and Aidy Bryant played coworkers who couldn't figure out how to do a Zoom video call. "We ruined the Zoom!" McKinnon's character cried.
Larry David made a memorable guest appearance as Bernie Sanders, who dropped out of the presidential race last week, and Alec Baldwin made a call-in appearance as President Trump. Chris Martin was the musical guest.
The show also featured a tribute to Hal Willner, the show's longtime musical coordinator, who died last week at age 64. "SNL" alums Tina Fey, Rachel Dratch, Amy Poehler, Maya Rudolph and others sang Lou Reed's "Perfect Day" in his honor.
One of the most memorable moments of the show came at the end of Hanks' monologue — when he got serious and thanked the men and women who are keeping our country going.
"Stay safe," he said. "We are in this for the duration, and we will get through this together."