Background: Diarrhea is the increase in the excretion of human water; meanwhile, fisetin, a bioactive flavonol molecule, is widely used in the treatment/prevention of gastrointestinal disorders. The purpose of this study is to investigate the anti-diarrheal activity of fisetin by restoring kidney function, antioxidant activity, inflammatory markers, Na{}^{+}/K{}^{+}-ATPase level, apoptosis, and protein content in diarrheal rats. Methods: A total of 36 male rats were distributed into two groups (18 rats/group): normal and diarrheal. The normal group was further divided into three subgroups (6 rats/subgroup): Control, fisetin, and desmopressin drug subgroups, consisting of normal rats orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. A lactose diet containing 35% lactose was fed to the normal rats for a month. The diarrheal rats were also divided into three subgroups (6 rats/subgroup): diarrheal rats, diarrheal rats + fisetin, and diarrheal rats + desmopressin drug groups, whereby the diarrheal rats were orally treated once a day for 4 weeks with 1 mL distilled water, 50 mg/kg fisetin, and 1 mg/kg desmopressin drug, respectively. Results: Fisetin significantly decreased serum urea (41.20 \pm 2.6–29.74 \pm 2.65), creatinine (1.43 \pm 0.05–0.79 \pm 0.06), and urinary volume (1.30 \pm 0.41–0.98 \pm 0.20), while significantly increasing kidney weight (0.48 \pm 0.03–0.67 \pm 0.07), sodium, potassium, and chloride balance in both serum and urine. Fisetin significantly increased the antioxidant activity (superoxide dismutase (1170 \pm 40–3230 \pm 50), glutathione peroxidase (365 \pm 18–775 \pm 16), catalase (0.09 \pm 0.03–0.14 \pm 0.06), and nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase activity (8.6 \pm 1.31–10.5 \pm 1.25), while significantly decreasing malondialdehyde (19.38 \pm 0.54–9.54 \pm 0.83), conjugated dienes (1.86 \pm 0.24–1.64 \pm 0.19), and oxidative index (0.62 \pm 0.04–0.54 \pm 0.05)), alongside the inflammatory markers (tumor necrosis factor-\alpha (65.2 \pm 2.59–45.3 \pm 2.64), interleukin-1\beta, interleukin-6 (107 \pm 4.5–56.1 \pm 7.2), and interleukin-10) in the diarrheal rats to values approaching the control values. Fisetin also restored the Na{}^{+}/K{}^{+}-ATPase level, apoptosis, protein content, and kidney architecture in diarrheal rats to be near the control group. Conclusions: Fisetin treated diarrhea in rats by restoring kidney function, antioxidant activity, inflammatory markers, apoptosis, proteome content, and histology.