Skeletal muscle degeneration (SMD) is a physiological condition characterized by decrease in muscle mass due to reduced protein synthesis and/or degradation. About 1 in 300 people is seen with a SDM. Chemotherapies generally used in the treatment of diseases like cancer and tuberculosis although expensive and inaccessible also contribute to SMD. Hence, the need to explore cheaper, safer and readily available options in Moringa oleifera leaf-based diet (MoLD). The objectives of the study were to: (i) identify the secondary metabolites in M. oleifera leaf; (ii) determine the proximate composition of MoLD; (iii) confirm the induction of skeletal muscle degeneration; (iv) evaluate the effects of MoLD on markers of muscle degeneration; and (v) evaluate the toxicity of MoLD in Wistar rats.rnSkeletal muscle degeneration was induced by maintaining adult rats on 4% low protein iso-caloric diets (LPID) for four weeks. The control animals were fed on soy-based meal only while the SMD-induced rats were maintained on soy-based diet supplemented with methyl jasmonate (100 μg/kg) + vitamin E (20 mg/kg) + carnitine (3 mg/kg) (Soy-based), 12.5% MoLD and 25% MoLD. The feeding was done for four weeks after which serum and hind limb skeletal muscle homogenates were prepared for biochemical analyses. Data was analyzed using one-way Analysis of Variance and Tukey’s posthoc test at p ˂ 0.05.rnThe findings of this study were that:rni. M. oleifera leaf contained terpenoids (2.91mg/g), tannins (9.2mg/g), flavonoids (12.5mg/g), total phenols (42.34mg/g), alkaloids (30.86μg/g) and saponins (55.22μg/g);rnii. the crude protein (13.77%) and carbohydrate (62.89%) contents of 25% MoLD was higher than those of 12.5% MoLD but was similar to the control;rniii. MoLD significantly (p ˂ 0.05) increased the activities of serum creatinine kinase (CK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and alanine transaminase (ALT) and reduced Ca2+- ATPase activity when compared with the control;rniv. activities of serum CK, LDH, AST and ALT were significantly (p ˂ 0.05) reduced by the 12.5% and 25% MoLD whereas these enzymes in animals fed soy-based were not comparable with the control;rnv. activity of cytosolic and mitochondrial Ca2+- ATPase was significantly increased by all the treatments in the order: Soy-based ˃ 25% MoLD ˃ 12.5% MoLD;rnvi. the 25% MoLD produced significantly (p ˂ 0.05) higher activities of superoxide dismutase, glutathione-S-transferase, glutathione (reduced) and malondialdehyde when compared with other treatments;rnvii. mitochondrial permeability and reactive oxygen species was significantly reduced while membrane potential was increased in all the treatment groups with the 25% MoLD producing the most profound change; andrnviii. activities of serum AST, ALT and alkaline phosphatase (ALP) as well as albumin, urea and creatinine concentrations in the 12.5% and 25% MoLD fed animals were not significantly different from those of the control whereas those of Soy-based were higher than the control values.rnThe study concluded that 25% MoLD ameliorated muscle degeneration in rats by positively modulating calcium homeostasis, oxidative stress, energy depletion and is also safe for consumption. The 25% M. oleifera leaf-based diet may be explored as an alternative therapeutic option for managing muscle degeneration.