The 31-year-old singer, who uses they/them pronouns and is non-binary, was bringing their tour in support of their fourth studio album Gloria when they stopped after the fourth song on Wednesday.
Prior to the concert, they teased a “surprise” at the Manchester AO Arena which appeared to suggest that 64-year-old American singer-songwriter Madonna would be joining them on stage.
In an Instagram story, they said: “Dearest sailors, I don’t know what to say honestly.
“I fought off a virus a few weeks ago and since then we have travelled across Europe and had such incredible shows.
“Today in soundcheck I felt fine and was so excited to give Manchester an amazing show tonight, with a special surprise at the end.
“During my third song, I noticed something wrong with my voice.
“I prayed it was just my voice waking up for the show but into the fourth song I could feel something was really wrong.
“I came off stage and have tried everything to get my voice back in gear but it won’t.
“I am honestly heartbroken I couldn’t finish the show tonight for you all.
“I love you all. I’m sorry, I’m sorry, I’m sorry x.”
Smith, who has had eight UK number one singles including Unholy and Too Good At Goodbyes, is set to play Ovo Hydro in Glasgow on Thursday and Resorts World Arena in Birmingham on Saturday.
The Brit-winning artist then has a series of festival dates in places such as Warsaw, Switzerland, Portugal and Latvia over June and July.
Smith had previously cancelled their Glasgow show at Ovo Hydro and Birmingham’s Resorts World Arena date in April due to illness.