Abstract: As the global exploration and development of oil and gas resources advances into deep formations, the harsh conditions of high temperature and high salinity present significant challenges for drilling fluids. In order to address the technical difficulties associated with the failure of the filtrate loss reducers under high-temperature and high-salinity conditions. In this study, a hydrophobic zwitterionic filtrate loss reducer (PDA) was synthesized based on N,N-dimethylacrylamide (DMAA), 2-acrylamido-2-methylpropane sulfonic acid (AMPS), diallyl dimethyl ammonium chloride (DMDAAC), styrene (ST) and a specialty vinyl monomer (A1). When the concentration of PDA was 3%, the FLAPI of PDA-WBDF was 9.8 mL and the FLHTHP (180 °C, 3.5 MPa) was 37.8 mL after aging at 240 °C for 16 h. In the saturated NaCl environment, the FLAPI of PDA-SWBDF was 4.0 mL and the FLHTHP (180 °C, 3.5 MPa) was 32.0 mL after aging at 220 °C for 16 h. Under high-temperature and high-salinity conditions, the combined effect of anti-polyelectrolyte and hydrophobic association allowed PDA to adsorb on the bentonite surface tightly. The sulfonic acid groups of PDA increased the negative electronegativity and the hydration film thickness on bentonite surface, which enhanced the colloidal stability, maintained the flattened lamellar structure of bentonite and formed an appropriate particle size distribution, resulting in the formation of dense mud cakes and reducing the filtration loss effectively.