Lady Gaga, Paul McCartney and Billie Eilish were among more than 100 artists who performed songs from their living rooms, due to the coronavirus lockdown.
The Rolling Stones even managed to play together from four separate locations.
The eight-hour show also featured real-life stories from those on the front line of the fight against Covid-19.
The event raised almost $128m (£102m), with proceeds going towards vaccine development and local and regional charities, organisers Global Citizen said.
Lady Gaga, who curated the line-up, called the event "a love letter to the world".
Dedicating the show to first responders and medical staff, she said the participating musicians all wanted "to give back a little bit of the kindness that you've given us".
She went on to play an upbeat version of Charlie Chaplin's Smile, adding: "We want to get to the other side of this pandemic and we know you do too."
Paul McCartney joined the programme shortly after, calling health-care workers "the real heroes" of the crisis and remembering his mother Mary, who was a nurse during the Second World War.
Titled One World: Together At Home, the concert was organised by the Global Citizen movement and the World Health Organization (WHO).
It began with a montage of people under lockdown applauding the efforts of healthcare workers around the world - from France, Spain, the UK, the 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.