This site had extensive maritime trade networks throughout Southeast Asia and with India, and is believed to have possibly been the ancient capital to the civilization of Funan.

Despite that, in 1421 Indravarman VI of Champa seized and annexed the eastern part of the Mekong Delta, including the marketplace town of Biên Hòa.

Earliest Vietnamese settlements in the Mekong Delta appeared and centered around Đồng Nai and Mỗi Xoài (today Bà Rịa–Vũng Tàu).

16 years later, the Nguyễn again militarily interfered Cambodian internal royal affairs, putting Prince Ang Nan into power.

In March, the Vietnamese expedition under Cảnh and a Chinese general Trần Thượng Xuyên (Chen Shangchuan) defeated the main Cambodian army at Bích Đôi citadel, king Chey Chettha IV took flight while his nephew Ang Em surrendered to the invaders as the Vietnamese captured Phnom Penh.

Under the reign of king Chey Chettha V, in 1750 he began subduing and persecuting the Cham–Malay Muslims, who at the time were close allies of the Nguyễn lords.

10,000 Vietnamese troops divided into two groups, rolled into Cambodia and completely flattened Cambodian resistance and easily captured its capital Phnom Penh in summer of 1754.

Due to heavy spring rain, the Muslim segment lost contact with the main army of Nguyễn Cư Trinh, and were surrounded by 10,000 Cambodians at Vô Tà Ân in early 1755.

Muslim troops piled carts and wagons into a defensive perimeter and stood their ground against Cambodian attacks until being relieved by Nguyễn Cư Trinh.

With the help of mediation by Mạc Thiên Tứ of Hà Tiên, a ceasefire agreement was reached between King Chey Chettha V and Lord Nguyễn Phúc Khoát in 1756: Cambodia ceded Gò Công and Tân An to the Vietnamese, Chey Chettha V was deposed, while Ang Tong was restored as King of Cambodia.

[15] In 1802 Nguyễn Ánh crowned himself emperor Gia Long and unified all the territories comprising modern Vietnam, including the Mekong Delta.

Brigadier General Lê Văn Hưng, the head of 21st Division commander, stayed office in Cần Thơ to continue defending successfully against VC.

On 29 April 1975, the last U.S. Consul General Terry McNamara and his diplomats evacuated by marine boat from Cần Thơ to the South China Sea.

[19] In Mỹ Tho, Brigadier General Trần Văn Hai, who was in charged protecting National Highway 4 (now NH1A) from Saigon to Cần Thơ, committed suicide.

The Mekong Delta, as a region, lies immediately to the west of Ho Chi Minh City (also called Saigon by locals), roughly forming a triangle stretching from Mỹ Tho in the east to Châu Đốc and Hà Tiên in the northwest, down to Cà Mau at the southernmost tip of Vietnam, and including the island of Phú Quốc.

[22] The Mekong Delta region of Vietnam displays a variety of physical landscapes, but is dominated by flat flood plains in the south, with a few hills in the north and west.

The soil of the lower Delta consists mainly of sediment from the Mekong and its tributaries, deposited over thousands of years as the river changed its course due to the flatness of the low-lying terrain.

[24][25] Historic sediment loads are estimated to be higher, but have been reduced due to damming for hydropower in the upper reaches of the Mekong River Basin, and sand mining in the riverbed.

[26] Sediment is the driving factor in building the delta seaward (progradation), and upward (aggradation) from seasonal flooding, and is counteracted by coastal erosion and sea level rise.

[27] The water entering the Gulf of Thailand was flowing via a palaeochannel located within the western part of the delta; north of the Camau Peninsula.

[28] Upper Pleistocene prodeltaic and delta front sediments interpreted as the deposits of the palaeo-Mekong River were reported from central basin of the Gulf of Thailand.

[32][33] Being a low-lying coastal region, the Mekong Delta is particularly susceptible to floods resulting from rises in sea level due to climate change.

The Khmer minority population live primarily in the Trà Vinh, Sóc Trăng, and Muslim Chăm in Tân Châu, An Giang and Cà Mau provinces.

[31] The Mekong Delta is by far Vietnam's most productive region in agriculture and aquaculture, while its role in industry and foreign direct investment (FDI) is much smaller.

It has almost half of Vietnam's capacity of offshore fishing vessels (mostly in Kien Gian with almost 1/4, Bến Tre, Cà Mau, Tiền Giang, Bạc Liêu).

[31] Despite the region's large offshore fishing fleet, 2/3 (2.13 million tonnes out of Vietnam's total of 2.93) of fishery output actually comes from aquaculture.

The bridge replaces the ferry system that currently runs along National Route 1, and links Vĩnh Long province and Cần Thơ city.

The cost of construction is estimated to be 4.842 trillion Vietnamese đồng (approximately 342.6 million United States dollars), making it the most expensive bridge in Vietnam.

[47] The Mekong Delta cuisine relies heavily on fresh products which is abundant in the new land with heavy use of seafoods and unique ingredients of the region such as palm sugar, basa fish and wild herbs and flowers such as điên điển, so đũa, kèo nèo.

Some Vietnamese films on the topic of life in the Mekong Delta attract the attention of a large audience: Tình Mẫu Tử (Mother and child love, 2019), Phận làm dâu (Bride's fate, 2018), etc.