© 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society. We compared the effects of an 8-week iso-caloric high-protein (HP) diet versus a combined exercise regimen (Comb-Ex) in individuals with long-standing spinal cord injury (SCI). Effects on metabolic profiles, markers of inflammation, and signaling proteins associated with glucose transporter 4 (GLUT-4) translocation in muscles were evaluated. Eleven participants with SCI completed the study (HP diet: n = 5; Comb-Ex: n = 6; 46 ± 8 years; C5-T12 levels; American Spinal Injury Association Impairment Scale A or B). The Comb-Ex regimen included upper body resistance training (RT) and neuromuscular electrical stimulation-induced-RT for paralytic quadriceps muscles, interspersed with high-intensity (80–90% VO2 peak) arm cranking exercises 3 days/week. The HP diet included ~30% total energy as protein (carbohydrate to protein ratio <1.5, ~30% energy from fat). Oral glucose tolerance tests and muscle biopsies of the vastus lateralis (VL) and deltoid muscles were performed before and after the trial. Fasting plasma glucose levels decreased in the Comb-Ex (P < 0.05) group compared to the HP-diet group. A decrease in areas under the curve for insulin and TNF-α concentrations was observed for all participants regardless of group assignment (time effect, P < 0.05). Although both groups exhibited a quantitative increase in insulin sensitivity as measured by the Matsuda Index, the change was clinically meaningful only in the HP diet group (HP diet: pre, 4.6; post, 11.6 vs. Comb-Ex: pre, 3.3; post, 4.6). No changes were observed in proteins associated with GLUT-4 translocation in VL or deltoid muscles. Our results suggest that the HP-diet and Comb-Ex regimen may improve insulin sensitivity and decrease TNF-α concentrations in individuals with SCI.