The Y oilfield reservoir is characterized by ultra-depleted reservoir and multiple pressure systems in each well section. If conventional PLUS/KCL drilling fluid is used in directional drilling, the following problems are found: the rheological stability of drilling fluid is not sufficient, resulting in increased viscosity and thickening after aging, and the single plugging material may cause loss-circulation when the drilling differential pressure is more than 26 MPa, resulting in poor reservoir protection effects. To solve the above problems, based on the conventional PLUS/KCL drilling fluid formula, a PLUS/KCL drilling fluid system suitable for directional drilling in multi-pressure systems was formed by optimizing the addition of a treating agent to improve the rheological stability of the drilling fluid, optimizing the plugging agent and compound combination to improve plugging ability, and optimizing the particle size distribution of a temporary plugging agent to improve the reservoir protection effect. The laboratory test evaluation showed that the optimized PLUS/KCL drilling fluid had fine plugging pressure capacity, and the intrusion depth was only 4.1 cm on the natural core at 120 °C/35 MPa/12 h, effectively reducing the risk of loss-circulation. The permeability recovery rate of the core after cutting off the polluted end was more than 90%, indicating that the reservoir protection effect was good. The drilling fluid performance was stable, and the cuttings rolling recovery rate was over 90%. Field application showed that the optimized PLUS/KCL drilling fluid was used without any loss-circulation or wellbore instability, and the production of all wells was over-matched, effectively solving the problem of ensuring drilling safety and reducing reservoir damage under the differential pressure of multiple pressure systems.