The route was suspended during the pandemic, but will resume on 1 December, flying in both directions on Wednesday, Friday and Sunday.
The airline’s general manager, UK and Ireland, Mohamed Rafi Mar, said: “We are delighted to resume our Houston flights and offer more travel options to our passengers from the Manchester region, after relaunching our flights to Singapore in the summer."
The flight will leave Manchester at 10.05, arriving Houston at 14.25. The return service will leave the US at 18.50, arriving at 09.30 the next day. Flights will be on an Airbus A350-900.
Houston is a key hub for Singapore Airlines’ Star Alliance partner United Airlines.