The Air India flight left Tan Son Nhat International Airport in Ho Chi Minh City for Mumbai and Cochin.
The passengers on board had been stranded in Vietnam after Vietnam closed its borders and suspended all international flights in an unprecedented move to contain the spread of the Covid-19 pandemic.
It was the first flight to repatriate Indians from Vietnam in the Vande Bharat Mission launched by the Indian government, its massive Covid-19-related repatriation program.
A second is expected to leave on June 29, also from HCMC. India is currently the largest Covid-19 hotspot in Asia, with over 240,000 infections and 6,700 deaths.
Last month 340 Vietnamese nationals stuck in India for months with a Covid-19 lockdown in place were brought home.
Vietnam suspended international flights on March 25, leaving thousands of foreigners stranded.
European countries, Australia and Russia too have arranged special flights to repatriate their citizens from Vietnam.
Sunday morning marked the 52nd day that Vietnam has gone without community transmission of the novel coronavirus. With 307 patients having recovered, there are 22 active patients in the country and no deaths.
The Covid-19 pandemic has affected 213 countries and territories, with more than 401,047 deaths reported.