Grande, her voice exhausted from the long evening, paused with tears in her eyes before the song's coda as the crowd, made up of people the same age as those who attended her concert in the area less than two weeks earlier, watched on - no doubt exhausted, but no less passionate for it.
The Manchester concert came the day after attackers targeted the heart of London, killing seven people.
Fans make a symbolic gesture at the One Love Manchester tribute.
"Manchester we're strong. we're still singing our song", he sang with the audience of 50,000.
According to Billboard, Grande performed some of her best hits including: "Be Alright", "Love Me Harder", "The Way", and "Break Free".
Sunday's concert will raise money for victims of the attack that struck at Grande's show on May 22.
British singer Marcus Mumford held a moment of silence before opening the benefit concert. The song includes the lyrics: "But you are not alone in this, and you are not alone in this, as brothers we will stand and we'll hold your hand". The attack killed 22 and wounded dozens.More news: Sailing-New Zealand pick Britain as America's Cup semi-final foe
Others to perform included Justin Bieber, Coldplay, Katy Perry, Usher and the Black Eyed Peas.
The show is being broadcast live across the globe.
The pop singer visited young fans injured in the attack at the Royal Manchester Children's Hospital on Friday.
The night was a massive success, managing to unify Britain in the wake of the terrorist attacks in both Manchester and London, and ahead of an increasingly tight General Election on Thursday.
"First show back tonight".
Ariana Grande paid tribute to the city of Manchester, England, on Sunday with an energetic, all-star concert that raised millions for victims of a suicide bombing that tore through her last performance in the city almost two weeks ago. On June 4th, the Manchester Arena featured appearances by Mac Miller, Justin Bieber, and Katy Perry, Miley Cyrus, and Pharrell. "Seeing you guys coming together was a sight to behold, we love you, we are with you, the whole world is watching", he told the crowd.