This paper presents a novel variable stiffness actuator (VSA) based on a cam-leaf spring mechanism, namely, CLSM-VSA. A sophisticatedly designed cam is used to regulate the transmission ratio between the deformation of the leaf spring and the deflection angle of the VSA, such that the stiffness profile of the actuator can be customized (linear, softening, or hardening). This property is meaningful for specific applications, e.g., VSAs with softening stiffness profiles help reduce the collision force, which is verified by our experiments. Moreover, the stiffness of the proposed actuator can also be continuously regulated by adjusting the location of the pivots that are in contact with the leaf springs. In this case, the stiffness not only can be changed passively with fast speed when the applied torque changes, but can also be regulated actively for different circumstances. Compared to other designs with similar output torque or power, the CLSM-VSA has the merits of compactness, low-power cost stiffness regulation, and high-power density. Additionally, the CLSM-VSA also features wide-range stiffness regulation, and the ratio between the maximum and minimum stiffness is approximately 20. The stiffness characteristics, control performances, and stiffness regulation efficiency of the proposed design are experimentally evaluated. Note to Practitioners—The VSA is a class of compliant actuators that can perform joint positioning and mechanical stiffness regulation, and its inherent compliance makes it suitable for robotics that have physical interaction with environments. In the design of VSAs, compactness and the capability of stiffness regulation are always the most critical features. This paper proposes a novel VSA based on a cam-leaf spring mechanism, which can derive customized stiffness profiles for specific requirements, e.g., softening stiffness for enhancing collision safety. Additionally, we can also actively regulate the actuator stiffness by using a stiffness r...