A mass mortality event involving cultured blood cockles (Tegillarca granosa) occurred in the Welu estuary in Chanthaburi Province, Thailand, during July and early August of 2013. We collected surviving blood cockles (n = 30) shortly after the mortality event in mid-August and evaluated the physiological conditions of the specimens by performing histological observations of various organs. We found that most specimens of both sexes were at the peak of spawning. Histological observations revealed an absence of food in their digestive ducts and flattened epithelial cells in their midgut glands. The specimens had been experiencing low food availability and nutrient uptake. In addition, rainfall data for Chanthaburi Province revealed that the rainfall in July 2013 was more than twice the average amount received in previous years, and surface salinity data from around the aquaculture site revealed that salinity was < 10 Practical Salinity Unit for longer than a month. Therefore, we concluded that prolonged low-salinity conditions were a major cause of this mass mortality event.