In order to prepare a temperature-resistant and salt-resistant fluid loss agent for drilling fluid，polymer microsphere（PMS）was prepared with acrylamide，acrylic acid and multifunctional acrylate as the main raw materials. The linear polymer（PAAN）was synthesized with acrylamide，2-acrylamido-2-methyl-1-propanesulfonic acid and N-vinyl-2-pyrrolidone，and the polymer microsphere compound fluid loss agent （CLS） was made by the method of compounding PMS and PAAN. The performance of CLS was evaluated by thermogravimetric analysis，scanning electron microscope，Zeta potential analysis and drilling fluid performance testing. The results showed that the compound fluid loss agent CLS composed of PMS and PAAN had a synergistic effect between the components，and the fluid loss reduction performance was better than that of any single component. CLS had little effect on the rheology of drilling fluid and had excellent fluid loss reduction effect. In a drilling fluid with a bentonite content of 4%，when the dosage of CLS was 0—1%，the apparent viscosity of drilling fluid changed within ±2.0 mPa·s. When the dosage of CLS was 0.6%，the fluid loss of drilling fluid could be reduced to 6.0 mL. The initial decomposition temperature of CLS was 276℃. After the drilling fluid composed of 4% bentonite and 1.2% CLS was aged at 180℃ for 16 h，the fluid loss remained at 9.0 mL. After adding 6% NaCl，the fluid loss only changed from 5.5 mL to 7.0 mL，showing excellent temperature and salt resistance.