Oil-based drilling fluid is currently widely utilized when drilling shale, in which the oleophilic nano-plugging agent is the major component for wellbore strengthening. However, there have been few effective and straightforward evaluation methods for the nano-plugging agent. In this study, an artificial filter cake was created to simulate the microfissure of shale formation, and the performance of the nano-plugging agent was assessed using the fluid-loss reduction rate as the index. The filter cake was made from compound crystal weights and a high molecular weight polymer, and a nano-plugging agent matching the formation pore structures was selected. The performance of three plugging agents with varying particle sizes (ultrafine CaCO3, emulsified modified rubber MORLF, ULIA nano-plugging agent) was compared. Moreover, the validity of the evaluation process was confirmed, and the underlying plugging mechanism was investigated. The proposed technique can produce an artificial filter cake with a constant thickness of 3 × 10−3 m and a permeability in the range of 10−18 to 10−19 m2, and the assessment approach is consistent, precise and easy to use. This work may provide a guideline for evaluating oleophilic nano-plugging agents in the laboratory and field applications.