Aims The current study investigated the potential molecular mechanisms of telmisartan and vitamin D3 against the progression of skeletal muscle injury in a metabolic syndrome (MetS) rat model and the capacity of vitamin D3 to potentiate telmisartan effects. Main methods This 12-week study comprised a 6-week induction phase to establish MetS, followed by a 6-week treatment phase. MetS was induced by supplementing drinking water with 10 % fructose and providing a diet enriched with 24 % fat and 3 % NaCl. Following the induction phase and along with fructose/fat/NaCl feeding, MetS rats exhibiting weight gain, dysglycemia, atherogenic dyslipidemia, hyperuricemia, hypertension, and soleus muscle dysfunction were treated orally with telmisartan (5 mg/kg), vitamin D3 (10 μg/kg) or both daily for an additional 6 weeks before sacrifice. Key findings MetS rats exhibited increased soleus muscle oxidative stress, inflammation, and insulin resistance, accompanied by functional decline and structural damages (interstitial edema, leukocytic infiltration, degenerative myopathy, and fibrosis). Telmisartan and vitamin D3 significantly mitigated these detrimental effects. While telmisartan demonstrated broad protective effects, it failed to combat the MetS-induced muscular fibrosis. Conversely, vitamin D3 played a prominent anti-fibrotic role, which significantly contributed to the observed functional and structural recovery of MetS-induced skeletal muscle damage. Significance Our data provide a molecular basis for treating MetS-induced skeletal muscle injury through the co-administration of vitamin D3 and telmisartan, a unique angiotensin II type 1 receptor (AT1 receptor) blocker and partial peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. A new insight has been introduced into PPAR-γ/AT1 receptor/glucose transporter type 4 (GLUT4) axis.