Mỹ Tho was founded in the 1680s by Chinese refugees fleeing Taiwan when the general of the Qing Dynasty Shi Langdefeated the remnants of Southern Ming Dynasty in 1683. The area, at the time, was once part of the Khmer kingdom and it was annexed to Vietnam in the 18th century. The city is named after the Mỹ Tho river, which means Beautiful (Mỹ) Reed (Tho). Due to its proximity to Saigon, Mỹ Tho was the traditional gateway to the Mekong Delta. In the 17th century, the city had become one of the biggest commercial hubs in today's Southern Vietnam.
In 1860s, Mỹ Tho, along with Saigon, was a major strategic city during the French colonial campaign towards Vietnam. In 1862, France's capture of Mỹ Tho is regarded as the conclusion to the establishment of the French colony of Cochinchina, a development that inaugurated nearly a century of French colonial dominance in Vietnam. During the colonization period, the economy continued to prosper, attracting more immigrants, mainly from Teochew and Minnan. In 1876, Mỹ Tho province was established as one of six provinces in southeast Vietnam.