Background: Benzo[a]pyrene (B[a]p) is regarded as a polycyclic aromatic hydrocarbon that results due to partial combustion of organic materials.  B[a]p has variable probable toxic health effects on humans and that makes it an issue of concern to the public health. Spirulina Platensis is a type of cyanobacteria that is multicellular and filamentous, and it has gained considerable popularity in the field of medicine. Aim of the work: was to assess the potential protection by Spirulina against toxic effects of B[a]p in rats' heart tissues. Material and Methods: Fifty adult male albino rats have been categorized into 5 equal groups; Negative control, Positive control (10 mL/kg corn oil), Spirulina Platensis (300 mg/kg), Benzo[a]pyrene (50 mg/kg), and Benzo[a]pyrene + Spirulina Platensis groups. All treatments were given twice per week. After four weeks, rats had been sacrificed, NADPH oxidase-2 (NOX-2), malondialdehyde (MDA), nitric oxide (NO), reduced glutathione (GSH), superoxide dismutase (SOD), along with cytokines of inflammation; tumor necrosis factor-alfa (TNF-α) and interleukin-6 (IL-6) were measured in the heart. Determination of cardiac Toll-like receptor 4 (TLR4) by real-time polymerase chain reaction (RT-PCR) was also done. The left ventricular cardiac tissues were stained by both hematoxylin and eosin and Mallory trichrome stains, and the immunohistochemical expression of Connexin 43 (Cx43) was evaluated. Results: B[a]p-treated rats showed an elevation of oxidative and inflammatory markers, and increased expression of cardiac TLR4. Co-administration of Spirulina with B[a]p mitigated all the measured parameters. Histopathology and immunohistochemical staining showed that the B[a]p developed histological damage and immunohistochemical changes in the left ventricular tissues and these changes were alleviated by Spirulina co-administration. Conclusion: Administration of Spirulina produced positive impact on oxidative and inflammatory markers of the heart, along with ameliorating the histopathological and immunohistochemical findings induced by B[a]p. Recommendations: Spirulina Platensis is a suggested agent for protection against cardiotoxic effects of B[a]p. More studies are required to investigate cardio-protective potential as well as safe and effective doses in humans.