Soft actuators are essential to soft robots and can also be used with rigid-bodied robots. This paper is focused on methods for improving the applicability of origami-inspired soft pneumatic actuators (OSPA). Our method for rapidly fabricating OSPA is shown to be capable of making a range of actuator sizes out of different materials. The largest OSPA has a force-to-weight ratio of 124, and can lift a 44 kg mass using a −85 kPa supply pressure. Experiments with a smaller OSPA demonstrate that it can perform 150,000 contraction/extension cycles while carrying a 2 kg mass with minimal degradation due to its materials and design. Compared to other OSPAs for which fatigue tests were reported, our accordion pattern OSPA has the best values of work-to-mass ratio, max. force, and fatigue life. A computationally efficient FEA-based constrained optimization method for maximizing an OSPA’s work output is then proposed. A 55% improvement in the work output was predicted, while validation experiments with OSPA prototypes showed a 53% improvement. While these improvement percentages are very similar, the values of the predicted stroke and work output are about 16% larger than the experimental values. The optimization requires only ~5 h to run on a common laptop.