Boris Johnson has said it was "only sensible" to cancel his trip to India, due to take place next Monday.
India has been reporting more than 200,000 cases daily and has been added to the UK's "red list", meaning people returning from there must quarantine in a hotel for 10 days.
The PM said he would instead speak to his counterpart Narendra Modi online.
The trip - aimed at boosting trade and investment ties - had originally been due to take place in January.
But it was called off because of the UK lockdown.
The second cancellation comes as a Covid variant is spreading in India, with its government confirming 1,620 deaths from the virus on Sunday.
The capital Delhi has been put into lockdown.
UK health officials are investigating whether the variant, first found in India, spreads more easily and is able to resist the vaccine.
Public Health England says 103 cases have been detected in England, with four more recorded in Scotland.
Speaking on a visit to Bath, Labour leader Sir Keir Starmer said: "You can see around the world that the virus is still going up in a number of places. We need to be very careful about that."
Asked about his cancelled India visit, the prime minister said it was "frustrating" but "Narendra Modi and I have basically come to the conclusion that, very sadly, I won't be able to go ahead with the trip.
"I do think it's only sensible to postpone, given what's happened in India, the shape of the pandemic there."
The prime minister added that countries around the world had "a massive amount of sympathy with India, what they're going through", and that the UK's relationship with India was of "huge importance".
The trip - billed as Mr Johnson's first major overseas visit since entering Downing Street - had been set up to move the two countries nearer to a post-Brexit trade agreement.
To cancel one prime ministerial trip to India is unfortunate. To cancel twice is…
The government wants a trade deal with Delhi. Or to start talks about a trade deal with Delhi, at the very least.
That could become a little bit harder now that Boris Johnson's tour has been cancelled for a second time.
Hence why the prime minister wants to keep up the contact with his counterpart Narendra Modi virtually, and is flagging other opportunities for them to meet face to face, such as this summer's G7 summit in Cornwall.
But is that meeting now in doubt, as coronavirus interrupts the travel plans of world leaders just as much as the rest of us?
And some observers say that the logistics of dealing with India is the easy part, and negotiating a trade deal will be significantly harder.
Last week, Downing Street said it would be scaled down - with the bulk of the meetings taking place on Monday 26 April, rather than across four days as originally planned.
But Labour argued the trip should be cancelled entirely and that the two prime ministers should talk via Zoom.
One senior Conservative also told the BBC it would have been "absurd" for the trip go ahead.
The prime minister's official spokesman said there was not "one single factor" behind the cancellation, but the situation in India was "challenging" and that it was "not the right time for a visit."
He added that Mr Johnson and Mr Modi would meet in person later this year.