An awareness of sex differences in gait can be beneficial for detecting the early stages of gait abnormalities that may lead to pathology. The same may be true for wheelchair propulsion. The aim of this study was to determine the effect of sex on wheelchair biomechanics and mechanical efficiency in novice young able-bodied wheelchair propulsion. Thirty men and 30 women received 12 min of familiarisation training. Subsequently, they performed two 10-m propulsion tests to evaluate comfortable speed (CS). Additionally, they performed a 4-min submaximal propulsion test on a treadmill at CS, 125% and 145% of CS. Propulsion kinetics (via Smartwheel) and oxygen uptake were continuously measured in all tests and were used to determine gross mechanical efficiency (GE), net efficiency (NE) and fraction of effective force (FEF). Ratings of perceived exertion (RPE) were assessed directly after each trial. Results indicated that CS for men was faster (0.98 ± 0.24 m/s) compared to women (0.71 ± 0.18 m/s). A lower GE was found in women compared to men. Push percentage, push angle and local RPE were different across the three speeds and between men and women. NE and FEF were not different between groups. Thus, even though their CS was lower, women demonstrated a higher locally perceived exertion than men. The results suggest sex differences in propulsion characteristics and GE. These insights may aid in optimising wheelchair propulsion through proper training and advice to prevent injuries and improve performance. This is relevant in stimulating an active lifestyle for those with a disability.