The purpose of this study was to determine the effects of short-term (14-day) unilateral leg immobilization using a simple knee brace (60° flexion)- or crutch-mediated model on muscle function and morphology in men (M, n = 13) and women (W, n = 14). Isometric and isokinetic (concentric-slow, 0.52 rad/s and fast, 5.24 rad/s) knee extensor peak torque was determined at three time points (Pre, Day-2, and Day-14). At the same time points, magnetic resonance imaging was used to measure the cross-sectional area of the quadriceps femoris and dual-energy X-ray absorptiometry scanning was used to calculate leg lean mass. Muscle biopsies were taken from vastus lateralis at Pre and Day-14 for myosin ATPase and myosin heavy chain analysis. Women showed greater decreases (Pre vs. Day-14) compared with men in specific strength (N/cm2) for isometric [M = 3.1 ± 13.3, W = 17.1 ± 15.9%; P = 0.055 (mean ± SD)] and concentric-slow (M = 4.7 ± 11.3, W = 16.6 ± 18.4%; P < 0.05) contractions. There were no immobilization-induced sex-specific differences in the decrease in quadriceps femoris cross-sectional area (M = 5.7 ± 5.0, W = 5.9 ± 5.2%) or leg lean mass (M = 3.7 ± 4.2, W = 2.7 ± 2.8%). There were no fiber-type transformations, and the decreases in type I (M = 4.8 ± 5.0, W = 5.9 ± 3.4%), IIa (M = 7.9 ± 9.9, W = 8.8 ± 8.0%), and IIx (M = 10.7 ± 10.8, W = 10.8 ± 12.1%) fiber areas were similar between sexes. These findings indicate that immobilization-induced loss of knee extensor muscle strength is greater in women compared with men despite a similar extent of atrophy at the myofiber and whole muscle levels after 14 days of unilateral leg immobilization. Furthermore, we have described an effective and safe knee immobilization method that results in reductions in quadriceps muscle strength and size.