Background: Nanoparticles are increasingly exposed to ecosystems and people due to their large-scale manufacture and usage. The use of nanomaterials has increased their discharge into the aquatic environment.Objectives: This research evaluated the protective effect of Spirulina platensis against liver damage and oxidative stress in grey mullet (Mugil cephalus) after exposure to Iron oxide nanoparticles.Methods: Juvenile grey mullets were randomly classified into 12 equal groups: Group 0, 96h control group; Group 1, 60 days control group; Group 2, iron oxide nanoparticles (IONPs) at 15mg/kg for 96h; Group 3, IONPs at 15mg/kg for 60 days; Group 4, S. platensis at 300mg/kg for 96h; Group 5, S. platensis at 300mg/kg for 60 days, Group 6, IONPs at 15mg/kg+S. platensis at 300mg/kg for 96h; Group 7, IONPs at 15mg/kg+S. platensis at 300mg/kg for 60 days; Group 8, IONPs at 15mg/kg (for 2 weeks) followed by S. platensis at 300mg/kg for 96h; Group 9, IONPs at 15mg/kg (for 2 weeks) followed by S. platensis at 300mg/kg for 60 days; Group 10, S. platensis at 300mg/kg (for 2 weeks) followed by IONPs at 15mg/kg for 96h; Group 11, S. platensis at 300mg/kg (for 2 weeks) followed by IONPs at 15mg/kg for 60 days. At the end of the experiment, samples of the liver were extracted and subjected to analyses to measure reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA)Results: MDA levels in the liver were shown to have dramatically risen in the current investigation, but antioxidant SOD and GSH activity in the IONPs-treated group had significantly reduced compared to the controls. When compared to fish solely treated with IONPs, S. platensis treatment dramatically reduced liver MDA and CAT activity and raised SOD and GSH.Conclusion: All prior metrics significantly improved when IONPs-induced liver damage in fish was prevented by spirulina. By scavenging free radicals, reducing inflammation, and restoring endogenous antioxidant defense systems, S. platensis therapy has a protective effect in the liver of grey mullet against damage and oxidative stress in the IONPs.