Esophageal squamous cell carcinoma (ESCC), the most common pathological type of esophageal cancer, is one of the leading causes of cancer death worldwide, but an effective therapeutic avenue is still absent. This study was to evaluate the therapeutic effect of Agaricus blazei Murrill polysaccharides (ABP) and Enteromorpha prolifera polysaccharides (EP) on ESCC. The results showed that both ABP and EP have therapeutic effects on multiple malignant processes of ESCC, such as proliferation, migration, invasion, and apoptosis, in vitro. Moreover, both ABP and EP retard tumor growth in vivo and the growth of ESCC-derived organoids. A series of genes and proteins changed upon treatments with ABP and EP after RNA sequencing and proteomics analysis. Autophagy, mitophagy and ferroptosis were enriched after treatments with these two polysaccharides, suggesting that the consumption of ABP and EP may represent a promising dietary supplement for ESCC therapy.