The wavefront-sensing-based autofocus method can precisely determine the focal plane only with few captured images; however, the required phase retrieval, numerical wavefront propagation, and in-focus determination are often time consuming, inevitably limiting its high-speed applications. To accelerate its processing speed, the pixel-reduced wavefront-sensing-based autofocus (PRWSA) method is proposed: with field of interest selection as pixel reduction in the spatial domain and image compression as pixel reduction in the frequency domain, the wavefront with fewer pixels can be used for autofocusing, significantly decreasing the processing time. With simulations, pixel reduction criteria in both the spatial and frequency domains are first determined and tested; next certificated by experiments, the PRWSA method is proved to be well implemented for different specimens. Considering it can precisely locate the focal plane with simple setup, and accelerate the processing speed, this PRWSA method can be a potential tool for high-speed autofocusing.