The One World: Together At Home show will see more than 100 artists including the Rolling Stones and Billie Eilish play live from their homes.
Lady Gaga, who helped organise the concert, will also perform.
The eight-hour event run by the Global Citizen movement and the World Health Organization (WHO) is being live-streamed and broadcast on TV.
It began with a montage of people under lockdown applauding the efforts of healthcare workers around the world – from France, Spain, the UK and US and elsewhere.
“To all of our frontline healthcare workers, we are with you. Thank you for being there for us,” read an on-screen caption.
The event will also be telling real-life stories of nurses and doctors fighting the coronavirus outbreak.
Proceeds generated from the concert will go to the Covid-19 Solidarity Response Fund for the WHO, but Lady Gaga has made clear that the show is not a fundraising telethon and will focus on entertainment and messages of solidarity.
The event began with a six-hour pre-concert at 19:00 BST on Saturday, with a two-hour TV broadcast due to start at 01:00 BST on Sunday.
Kicking it off, actress Jameela Jamil said: “We are here for a moment of respite and hopefully joy as we celebrate our true heroes. Thank you for risking your lives every day to save the lives of others.”
First to perform was US singer songwriter Andra Day, who sang the ballad Rise Up from her apartment.
One Direction star Niall Horan followed shortly afterwards singing Black and White with an acoustic guitar from his living room and former bandmate Liam Payne followed later with the song Midnight. “It’s a pretty dark time for us all right now… and I feel we’re all being brought a lot closer together by this solidarity,” he said.
Two members of The Killers performed their hit Mr Brightside while US singer Adam Lambert gave a rendition of the Tears for Fears song Mad World and Jessie J sang Flashlight. Contributions were also expected from Sheryl Crow, Annie Lennox and Christine and the Queens.
Rita Ora urged viewers to stay safe and follow WHO recommendations, before singing I Will Never Let You Down.
“We may be apart right now, but coming together has never been more important,” Global Citizen said in a statement earlier.
American TV personalities Stephen Colbert, Jimmy Kimmel and Jimmy Fallon will host the main two-hour show, which will also feature Taylor Swift, Jennifer Lopez, Chris Martin, Pharrell Williams, Rita Ora, Sam Smith, Elton John and Paul McCartney.
The entire event is being streamed live on Amazon Prime Video, Facebook, Instagram, TuneIn, Twitch, Twitter and YouTube; with Apple, Music, Apple TV, and Apple Beats 1 joining for the main show.