Abstract: In order to solve the problem of wellbore instability in hard and brittle shale formations in Junggar Basin, the characteristics of mineral compositions and structural fabric of shale were analyzed, and the technology strategy with multi-scale tight plugging as the core was proposed according to the multivariate synergistic principle for wellbore stability. Furthermore, water-based drilling fluids (YHDF-1, YHDF-2) with multi-scale tight plugging were developed. From the analysis results of the mineral compositions and structural fabric characteristics, it is known that the wellbore instability of hard and brittle shales was closely related to its multi-scale characteristics of “microfracture–fissure–pore”. Therefore, the wellbore stability could be enhanced by plugging micro-nano scale fractures, improving shale hydration inhibitive ability, and offering effective stress support of drilling fluids with reasonable density. Performance evaluation results showed that YHDF-1 and YHDF-2 drilling fluids could withstand a high temperature up to 150 °C, and their PPA filtration volumes in a 400 mD sand disc were 17.8 mL and 13.2 mL respectively, with the shale permeability reduced by above 90%. YHDF-1 and YHDF-2 drilling fluids were applied in the drilling operation of Well D-72 and D-12 in Junggar Basin, and no wellbore instability occurred during the drilling process. The average well diameter enlargement rate was lower than 10% in all the test well sections, and the electrical logging was achieved successfully at a time. Research and field tests show that YHDF-1 and YHDF-2 drilling fluids exhibit excellent performance in plugging and collapse prevention, and can be used to deal with the wellbore instability of hard and brittle shale in Junggar Basin.