The singer spoke to Peaches, a young girl who lost her father during the Ebola crisis and was left without an adult to take care of her.
As he sang with her and listened to her story, he said witnessing the situation first hand was far worse than he had ever imagined.
And as he fought back the tears, viewers used Twitter to share how his piece had encouraged them to donate to Comic Relief.
One person commented: “Didn’t expect to turn the TV on and see Ed Sheeran crying and then Peaches crying and then me crying man.”
“Comic relief is fun n funny but stories like Ed Sheeran one with the young girl is the reason I donate every year bless her. Heartbreaking,” another posted.
Another added: “@edsheeran is a great ambassador for #comicrelief so normal, so humble - how different our lives could have been in another country! #donate.”
As the programme returned to the BBC studio, the Shape Of You singer gave a live performance, before sharing a kiss with actor Greg Davies.
Sheeran’s Liberian experience came as celebrities, performers and media figures gathered yesterday to boost fundraising efforts for Comic Relief, which was founded in 1985 by scriptwriter Richard Curtis and comedian Sir Lenny Henry in response to famine in Ethiopia. The total raised in 2015 was just under £100 million.
Among those taking part was Love Actually star Andrew Lincoln, who met fans ahead of the film’s Red Nose Day sequel.
Lincoln - who plays lovesick Mark in both the original film and the ten-minute follow-up - welcomed some of his US admirers as they made a sponsored pilgrimage around the movie’s most memorable London locations.
They visited St Luke’s Mews - where Lincoln presents his famous heart-warming cue cards to Keira Knightley’s character - and the bench at Gabriel’s Wharf where Liam Neeson’s character learns that his son is in love.
Emma Freud, meanwhile, promised that Take That’s Red Nose Day Carpool Karaoke appearance would be “brilliantly funny”.
The broadcaster urged viewers to tune in to the Comic Relief show to find out what makes the boy band’s feature special, adding that it was “not to be missed”. Sir Lenny said: “Tonight is an opportunity to save lives, to reach out in the spirit of partnership and compassion. The money you give tonight will make things better for people with tough lives here at home and abroad.”