Obesity is a complicated metabolic disorder characterized by abnormal or excessive fat accumulation in the body that may pose a higher risk for chronic diseases. The present study investigates the protective effects of Spirulina platensis extracts (SPEs) from both conventional and nano-formulated extraction against oxidative stress and liver function in rats with hyperlipidemia. Forty male albino rats were divided into five groups. The C group received normal saline only during the observation period. Hyperlipidemic group (T1) was treated with high fat diet (HFD) for 90 days without any medication. Group T2 was treated with the conventional ethanolic Spirulina extract (100 mg/kg/day) during the HFD. Group T3 was also administered Spirulina extract in a nano-form and in the same dose. Group T4 treated with ZnO-NPs (10 mg/kg/day) with HFD. Animals were treated for 30 days after hyperlipidemia induction. The body weight, and serum MDA, liver enzymes (ALT and AST) were significantly increased while antioxidant enzymes (GSH, CAT and SOD) were prominently reduced in T1 group, indicating oxidative damage. Spirulina treatment, particularly in nano-form (T3), resulted in remarkable enhancement in all previously evaluated parameters. The T3 treatment had the highest increment effect followed by the T2 and T4. This study concluded that nano-formulated Spirulina (T3) showed higher protection level compared to conventional form (T2) and ZnO-NPs (T4) implying that nanotechnology increases biological activity of natural antioxidants, especially under conditions associated with lipid accumulation and development of oxidative stress.