Conventional micron sealants are unable to effectively seal nanopores and fractures in shale formations, and the development of new nanomaterials has now become a major research focus to address the instability of shale gas wells. In this paper, oil-based drilling fluids (ODFs) sealants named SMEB (poly(styrene-methyl methacrylate-ethyl methacrylate-butyl acrylate)) were synthesized by free radical polymerization. The SMEB has been characterized by Fourier transform infrared spectroscopy (FTIR), laser scattering analysis (LSA), thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). The effect of SMEB on the rheological properties of drilling fluids was evaluated by assessing the changes in the rheological parameters of ODFs before and after aging. In addition, the sealing performance of SMEB in ODFs was investigated by high-temperature, high-pressure (HTHP) fluid loss tests and HTHP dense core permeability tests. The results indicated that the particle size of SMEB ranged from 60.68 to 157.39 nm, with a median size of 89.62 nm. The initial decomposition temperature of SMEB was 334 °C, which was in line with the requirement of high-temperature resistance for materials used in shale gas wells. The addition of SMEB has minimal effect on the rheological properties of the drilling fluids and did not adversely affect its performance. At 150 °C and 3.5 MPa, the sealing efficiency of the simulated mud cake was 59.69% with a measured permeability of 0.77 × 10 −4 mD at a concentration of 0.5 wt % SMEB. Additionally, when 0.5 wt % SMEB was applied to artificial cores at 105 °C and 3.5 MPa, the sealing efficiency was as high as 86.70%, and the corresponding permeability was 0.48 × 10 −3 mD. SMEB demonstrated excellent sealing capabilities in both simulated mud cake and artificial cores, reducing and preventing drilling fluids filtrate flow into the formation. Therefore, SMEB can be applied to drilling fluids as a novel sealing agent and make a significant contribution to maintaining wellbore stability.