To improve the autonomous flight capability of endo-atmospheric flight vehicles, such as cruise missiles, drones, and other small, low-cost unmanned aerial vehicles (UAVs), a novel minimum-effort waypoint-following differential geometric guidance law (MEWFDGGL) is proposed in this paper. Using the classical differential geometry curve theory, the optimal guidance problem of endo-atmospheric flight vehicles is transformed into an optimal space curve design problem, where the guidance command is the curvature. On the one hand, the change in speed of the flight vehicle is decoupled from the guidance problem. In this way, the widely adopted constant speed hypothesis in the process of designing the guidance law is eliminated, and, hence, the performance of the proposed MEWFDGGL is not influenced by the varying speed of the flight vehicle. On the other hand, considering the onboard computational burden, a suboptimal form of the MEWFDGGL is proposed to solve the problem, where both the complexity and the computational burden of the guidance law dramatically increase as the number of waypoints increases. The theoretical analysis demonstrates that both the original MEWFDGGL and its suboptimal form can be applied to general waypoint-following tasks with an arbitrary number of waypoints. Finally, the superiority and effectiveness of the proposed MEWFDGGL are verified by a numerical simulation and flight experiments.