The inaugural flight landed at Noi Bai International Airport in the Vietnamese capital on Thursday with 68 passengers, the airline said on its Facebook page.
There are three weekly flights using Airbus A320 aircraft on Tuesdays, Thursdays and Saturdays.
Situated in northwestern Cambodia, Siem Reap Province is home to the UNESCO heritage site Angkor Wat complex, the country's most popular tourist destination.
The carrier also plans to start direct flights from Siem Reap to Ho Chi Minh City and Da Nang.
Both Vietnam and Cambodia have reopened their borders and lifted most Covid restrictions.
Cambodia has become Vietnam's third largest source of foreign tourists post-reopening with 172,000 arrivals in the first 11 months of this year, behind only South Korea (760,000) and the U.S. (270,000), according to the General Statistics Office.
More than 180,000 Vietnamese have visited Cambodia, making Vietnam in turn one of the largest sources of tourists for that country.