India joined 189 members who voted on Thursday to urge the US to end the economic, commercial and financial embargo against Cuba.
Only the US and Israel voted against the resolution, and two other countries stayed away from the 193-member General Assembly.
Last December, the US was also isolated when the Assembly voted to criticise its decision to recognise Jerusalem as the capital of Israel and move its embassy to the disputed city sacred to three faiths.
As they did on Thursday, its closest European allies deserted the US on the vote on that resolution.
Although this was the 27th time the resolution on Cuba has been voted by the General Assembly, it took on new significance with US threats of sanctions against countries buying Iranian oil looming this Sunday.
The resolution, as before, also reiterated in general terms the principles of the sovereign equality of states and non-interference in their freedom of international trade and navigation in accordance with the UN Charter.
India, which faces prospects of US sanctions over buying oil from Iran and signing a deal to buy Russian anti-missile defence system valued at about $5 billion, spoke out during the debate on the resolution against countries unilaterally imposing sanctions.
Tanmaya Lal, India's Deputy Permanent Representative, declared on Wednesday that "India stands in solidarity with this Assembly in its unambiguous rejection of domestic laws having extraterritorial impact".
The US proposed eight amendments amendments to the resolution criticising Cuba's human rights record and the absence of women in senior government positions and demanding the release of political prisoners.
All of them were defeated.
US Permanent Representative Nikki Haley dismissed the resolution as a waste of time, saying: "It's one more time that countries feel they can poke the United States in the eye. But you're not hurting the US when you do this. You are literally hurting the Cuban people."
Cuban Foreign Minister Bruno Rodriguez called the US sanctions "an act of economic war" and an "aggression" that violated the UN Charter.
Former President Barack Obama began a process of normalising ties with Cuba in 2015 by restoring diplomatic relations cut off in 1961 and relaxing travel and some economic and financial restrictions.
But Trump changed course and reinstated some of the restrictions.