"It's nice to see you, Kamala," Harris tells actor Maya Rudolph, who plays Harris on the show, as they both appeared in the 'cold open'.
Harris portrayed herself, appearing in a mirror as Rudolph, nervously prepared for a campaign speech.
Dressed identically in a black suit and pearls, the two traded variations on Harris' first name, saying Americans want to "end the drama-la" in politics "with a cool new stepmom-ala."
"Keep calm-ala and carry on-ala," Harris said in unison with Rudolph.
"I'm going to vote for us," said Rudolph.
"Great, any chance you are registered in Pennsylvania?" Harris replied.
Other actors played Joe Biden, Donald Trump, JD Vance and Doug Emhoff, Harris' husband.
This will be Harris' first time on the NBC-TV comedy and political satire show, which is set to start shortly, at 11:30 p.m. ET
She has been preparing for her appearance for the past couple of hours, a campaign official said.
Harris is expected to appear in the "cold open," a narrative technique that dives straight into the story before the opening credits roll, the official said.
It follows in the footsteps of past candidates, including Trump himself.
In October 2015, then-Secretary of State Hillary Clinton appeared as she was preparing to engage in a string of Democratic primaries early the following year.
Clinton, playing a bartender, was told by an SNL cast member that she was "really easy to talk to." Clinton, in character, responded, "That's the first time I've ever heard that" - a dig at her reputation for appearing icy in public.
The following month, the long-running late-night show gave equal time to Trump, who would beat Clinton in the 2016 election, appearing in a sketch looking ahead two years into a White House term.
"I don't have to get specific" about policy, the future Trump said in a riff about his lack of experience in politics and governance.
Trump's daughter, Ivanka Trump, who in real life later landed a high-level White House job during her father's presidency, played his secretary of the interior, saying the Washington Monument was now blanketed in gold-mirrored glass, mocking her father's penchant for opulence.
While the sketch got some laughs, it prompted outrage from Latino activists who protested what they called Trump's racist views on immigration.
And then there was former Republican vice presidential candidate Sarah Palin, who appeared on a 40th anniversary SNL show in 2015 at a time when there was speculation that she was mulling a White House run - only to claim on the show that she would consider Trump as her vice presidential running mate.
The fiction failed to become fact, as Palin never joined the presidential race.
SNL separately hosted both Democratic candidate Barack Obama and Republican candidate John McCain in 2008.
