Background and Purpose: Some studies showed that fluoxetine has some promising properties in the treatment of specific infections; however, its effects have not been studied in the sepsis model. This research aims to investigate the effect of fluoxetine on the inflammatory process in a sepsis model in rats and to investigate its efficacy in modifying the antibiotic effect of imipenem. Experimental Approach: 40 rats were equally divided into five groups. The first group is as a negative control, group 2 is a positive control, group 3 treated with fluoxetine 5mg/kg, group 4 treated with Imipenem antibiotic 60mg/kg, and group 5 treated with fluoxetine combined with imipenem for 72 hours. The expression level of serum and tissue HsCRP, pro-calcitonin (PCT), lactate, myeloperoxidase activity (MPO), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor (TNFα), and monocyte chemoattractant protein-1 (MCP-1) was measured using ELISA. Oxidative stress markers were measured using photometric methods, total thiol (TT), native thiol (NT), total oxidant status (TOS), and total antioxidant status (TAS). Total tissue protein concentrations were measured by the Bradford method. Key Results: In fluoxetine, imipenem, and combined (fluoxetine + imipenem) groups, the IL-1β, IL-6, TNF-α, MPO, MCP-1, HsCRP, PCT, lactate, TOS, OSI, and disulfide levels were reduced (p<0.05). The antioxidant indicator (TT, NT, and TAS) levels significantly increased (p<0.05). Fluoxetine and imipenem combined therapy showed positive synergistic effects. Conclusion and Implications: This research shows that fluoxetine has an anti-inflammatory and antioxidant effect and its combined therapy with imipenem shows positive synergistic effects in the experimental sepsis model.