Most exoskeletons designed to assist users in load-bearing tasks face a mechanical dilemma in their conception. Designers may find a compromise between stiff active actuators-based architectures which are powerful but bulky and compliant actuator-based designs which are much less assistive but less constraining for users. This article presents a new open-source simulation-based design tool and a human-centered method that lets orthosis designers explore different device configurations and evaluate some performance criteria. This framework was applied in three different young-adult subjects. The effects of design personalization on user morphology and gait were studied. First, an ankle–foot orthosis designed to support a 20 kg backpack was defined according to the user’s height, weight, and walking speed. Then, a simulation of the subjects fitted with their customized design walking at a self-selected speed on flat ground carrying this additional load was performed. First, the results showed that the designed method inspired by natural joint stiffness behavior provided viable personalized mechanisms. Second, significant reductions in peak joint torque and mean joint activity were observed when comparing muscle-generated torques while the subject was wearing the 20 kg backpack with ankle–foot orthoses on both legs or without. Finally, it shows the value of an open-access tool for exploring the coupling of passive and active actuators to generate lighter and more compliant designs.