This study investigates the potential protective effects of Spirulina platensis (S. platensis), pomegranate peel extract (PPE), and their combination against heavy metal mixture (HMM)-induced hepatotoxicity. Fifty male albino rats were randomly allocated into five groups. Group 1 (control) received distilled water (1.5 mL/kg, orally). Groups 2-5 administered orally a mixture of lead acetate (40 mg/kg), mercuric chloride (1.0 mg/kg), and cadmium chloride (2.30 mg/kg) four days/week for nine weeks. One hour before HMM administration, rats in groups 3, 4, and 5 received PPE (500 mg/kg), S. platensis (150 mg/kg), and their combination, respectively, for the same duration. Liver sections of intoxicated rats revealed hepatocellular degeneration and necrosis, and occasional chronic cholangitis. Liver fibrosis with a noticeable increase in the Masson trichrome-stained collagen fibers in the portal areas was recorded. The immunohistochemical study revealed that the area % of α-SMA immunoreactivity in the liver of the HMM-intoxicated rats was significantly higher than the control. PPE, S. platensis, and their combination co-treatment significantly attenuated this hepatic cell damage, lessened liver fibrosis, and reduced α-SMA immunoexpression compared to the intoxicated group. In conclusion, both PPE and S. platensis conferred hepatic protection; however, Spirulina exerted greater efficacy in attenuating liver fibrosis. Furthermore, their combination demonstrated a synergistically stronger hepatoprotective impact.