Shrimp aquaculture suffers from white spot syndrome virus (WSSV) outbreaks and acute hepatopancreatic necrosis disease (AHPND). Currently, pond management is the key to preventing WSSV and AHPND, as there is no effective agent to prevent or cure these diseases. Sulfated polysaccharides are known to be part of the infective mechanism of many pathogens and essential to host immune responses. This work investigates the protective effects of dextran sulfate and heparin against WSSV and Vibrio parahaemolyticus, causing AHPND, in white shrimp Litopenaeus vannamei. After feeding shrimp with either 1%(w/w) dextran sulfate or 0.1%(w/w) heparin, proPO activity in the white shrimp and the expression levels of proPO1, proPO2, lyso2, pen3 and alf1 significantly increased. Both sulfated sugars showed a protective effect against WSSV. In addition, the microbiota of shrimp fed with dextran sulfate and heparin was reported. The dominant phyla in all samples was Proteobacteria. There was no significant differentiation among most of the alpha diversity indices. However, the effects of sulfated polysaccharide feeding by times on alpha diversity were observed on Day 3 and Day 14.