It is anticipated that flywheel-based leg resistance exercise will be implemented in future long-duration space missions, to counter deconditioning of weight-bearing bones and postural muscles. The aim was to examine low back loads and muscle engagements during flywheel leg press (FWLP) and flywheel squat (FWS) and, for comparisons, free-weight barbell back squat (BBS). Eight resistance-trained subjects performed 8 repetition maximums of FWLP, FWS, and BBS. Motion analysis and inverse dynamics-based musculoskeletal modeling were used to compute joint loads and muscle forces. Muscle activities were measured with electromyography (EMG). At the L4–L5 level, peak vertebral compression force was similarly high in all exercise modes, whereas peak vertebral posteroanterior shear force was greater (p < 0.05) in FWLP and BBS than in FWS. Among the back-extensor muscles, the erector spinae longissimus exerted the greatest peak force, with no difference between exercises. Peak force in the lumbar multifidus was lower (p < 0.05) during FWLP than during FWS and BBS. Peak EMG activity in the lumbar extensor muscles ranged between 31 and 122% of maximal voluntary isometric contraction across muscles and exercise modes, with the greatest levels in the lumbar multifidus. The vertebral compression forces and muscle activations during the flywheel exercises were sufficiently high to presume that when implementing such exercise in space countermeasure regimens, they may be capable of preventing muscle atrophy and vertebral demineralization in the lumbar region.