In this paper, nano plugging agent AMPS/AM was prepared, and its plugging performance was evaluated by a microfracture simulation experiment and a shale pressure resistance experiment. The pressure loss decreased by 66.09% compared with the top pressure of 6.9 MPa, and the average core indentation hardness increased 58.12% with 3% AMPS/AM blocking mud. The experiments indicate that AMPS/AM can effectively seal the shale micropore and nanopore structure and greatly improve the stability of fractured shale well wall. The field application results of the YS129H well in the Zhaotong block show that the water-based drilling fluid with nano plugging agent AMPS/AM as the key agent has strong plugging performance. The well mud is of high temperature and pressure water loss <4 mL, mud cake permeability reduction rate of 85.67%, which indicates that the drilling fluid system has good sealing properties and well wall stability.