Sepsis remains a major problem for both scientists and clinicians. Cecal ligation and puncture (CLP) is considered the gold standard for animal models of sepsis. The undesirable side effects of certain antibiotics have forced scientists to discover new, natural, and safe antimicrobial agents, such as cephalopods, which are known to display significant antimicrobial activity.The present investigation aims to evaluate the in vitro and in vivo antibacterial and antiseptic efficacy of Sepia officinalis body tissue (SOBT) extract and S. officinalis polysaccharide (SOP) from its cuttlebone.Forty-eight rats were divided into 4 groups, and starting 2 hours after CLP, treatments were given for 2 days as follows: sham control rats treated orally with distilled water, septic rats treated orally distilled water, septic rats treated orally methanolic extract of SOBT (500 mg/kg b.wt) suspended in distilled water, and septic rats treated orally SOP extract (200 mg /kg b.wt) dissolved in distilled water. On the third day, half of the rats in each group were euthanized for blood collection. The other half were kept alive and used for the survival study.The present study revealed that the SOBT and SOP extracts showed in vitro bactericidal activity against gram-positive and gram-negative bacteria. Furthermore, administration of SOBT and SOP increased the rats' survival rates by 66.7% and 83.33%, respectively, as compared to the untreated CLP-septic rats. Treatment of the CLP-septic rats with SOBT and SOP significantly alleviated alterations in procalcitonin levels and in some hematological parameters induced by CLP.SOBT and SOP had profound antiseptic efficacy.