This study investigated the protective properties of Lepidium draba L. hydroalcoholic extract (LDHE) against enterocolitis induced by Capecitabine (CT), utilizing biochemical, molecular, and histopathological analyses. A study was conducted involving 50 Wistar rats divided into 5 groups of ten rats over 60 days: healthy, 400 mg/kg LDHE, 20 mg/kg CT, and two co-treatment groups receiving both CT and 200 and 400 mg/kg LDHE groups. On the 61st day, serum nitric oxide, antidiuretic hormone (ADH), arginine vasopressin (AVP), tumor necrosis factor-α, interleukin-6, chemokine C-X-C motif ligand 1 (CXCL-1), and interleukin-1β levels were measured, along with the activity of glutathione peroxidase, catalase, and superoxide dismutase enzymes. To evaluate tissue oxidative stress in the intestine, measurements were taken for FRAP, thiol, and TBARS levels. Apoptosis in the intestine was assessed by examining the Bax/Bcl-2, caspase-3, and p53 expression via real-time PCR. Furthermore, real-time PCR was employed to evaluate water homeostasis by examining the AQP3, AQP8, and AQP10 expression, while protein expression was analyzed using western blotting. LDHE extract effectively regulates inflammatory cytokine levels and modulates ADH and AVP levels, thereby preserving serum and intestinal osmotic balance. Furthermore, it attenuated the Bax/Bcl-2, caspase-3, and p53 mitochondrial apoptotic pathways while enhancing the expression of AQP3, AQP8, and AQP10 genes in intestinal tissue. The study suggests that LDHE holds promise in the treatment of enterocolitis in chemotherapy patients.