This paper presents the authors’ investigation results of applying the pneumatic artificial muscle actuation to above-knee prostheses. As a well-known muscle actuator, the pneumatic artificial muscle actuator features a number of unique advantages, including high power density, and similar elastic characteristics to biological muscles. Despite multiple applications in related areas, the application of pneumatic artificial muscle in above-knee prostheses has not been explored. Inspired by this fact, the research presented in this paper aims to develop a pneumatic artificial muscle-actuated above-knee prosthesis, with three specific objectives: (1) demonstrate the pneumatic artificial muscle actuation’s capability in generating sufficient torque output to meet the locomotive requirements; (2) develop an effective control approach to enable the restoration of locomotive functions; (3) conduct preliminary testing of the prosthesis prototype on a healthy subject through a specially designed able-body adaptor. In the prosthesis design, an agonist–antagonist layout is utilized to obtain a bidirectional motion. To minimize the radial profile, an open-frame structure is used, with the purpose of allowing the expansion of the muscle actuators into the center space without interference. Also, the muscle actuator parameters are calculated to provide sufficient torque capacity (up to 140 N m) to meet the requirements of level walking. According to this design, the fabricated prototype weighs approximately 3 kg, with a range of motion of approximately 100°. For the control of the prosthesis, a model-based torque control algorithm is developed based on the sliding mode control approach, which provides robust torque control for this highly nonlinear system. Combining this torque control algorithm with an impedance-based torque command generator (higher-level control algorithm), the fabricated prosthesis prototype has demonstrated a capability of providing a natural gait during treadmill walking experiments.