The kidneys have a regulatory role in many diseases with their diuresis function and capacity to maintain electrolyte balance. In case of extensive damage, the kidney’s filtration capacity is impaired and cannot fulfill its functions. Fluvoxamine (FLV), an antidepressant agent, has antioxidant and anti-inflammatory effects. This study aimed to investigate the protective effects of FLV against renal tissue damage in the lipopolysaccharide (LPS) induced systemic inflammation model. Thirty-two Wistar Albino rats were divided into four equal groups: control, LPS, LPS + FLV, and FLV alone. Six hours after LPS administration, rats were sacrificed and kidney tissues were removed. Histopathological examination of kidney tissues, immunohistochemical expression of the ACE-1, Cas-9, and interleukin-10 (IL-10), as well as spectrophotometric assessment of total oxidant status (TOS), total antioxidant status (TAS), oxidative stress index (OSI), urea, creatinine levels, and zonulin-1 (ZO-1), claudin-5 (CL-5), aquaporins 2 and 4 (AQ-2, AQ-4) were evaluated. TOS, OSI, urea, creatinine levels, and Cas-9 expressions were significantly increased, and TAS levels, ACE-1, IL-10, AQ-2, AQ-4, ZO-1, and CL-5 expressions significantly decreased in the LPS group compared with the control group. In addition, marked hyperemia, slight-to-moderate hemorrhages, and degeneration of the tubule epithelial cells were observed in kidney sections in the LPS group, in addition to the inflammatory cell infiltrations. FLV treatment significantly improved all these findings. FLV treatment ameliorates renal tissues against inflammatory scenes and protects renal function by enhancing IL-10 and ACE-1 expressions and preserving AQ-2, AQ-4, CL-5, and ZO-1 expressions.