Objective Immunomodulation is a therapeutic technique that modulates the balance of cytokines in the body. In this regard, our experiment was conducted to investigate the potential effect of S. coronopifolius crude extract in combination with low dose of Bacillus Calmette- Guerin (BCG) on depression-like behaviors in female Wistar rats. Methods Sciatic nerve injury was employed to induce depression and intradermal injection of 0.02 mL of BCG per rat was administered to lead an activation of innate immune system. Daily intra-peritoneal injections of 25 mg algae extract kg-1 body weight were performed for 14 continuous days. Forced Swimming (FS) and Open Field (OF) tests were conducted to assess despairing and spontaneous behaviors. At the end of the experiment, brain was removed to determine the activities of catalase (CAT) and glutathione-S-transferase (GST), whereas spleen and adrenals were used for the histopathological study. Results The combined treatment exhibited antidepressant-like activity in FST by reducing immobility time, without inducing any significant change in ambulatory behavior in OFT. The histological analyses of spleen and adrenal structure showed a conserved architecture. Conclusion The results suggested that algae extract produce an antidepressant-like effect in combination with low dose of BCG, which is possibly trigged by its anti-oxidant and anti-inflammatory properties.