Traditionally, the usage of Citrullus colocynthis (CCT) causes severe side effects. The side effects of CCT fruit extract administered orally at different doses related to gastric tissues and circulating cytokines profiles were reported. Thirty-five adult male albino mice were divided into 4 groups, a control group (G1) and three experimental groups. They orally received aqueous fruit extract over 20 days at different doses; 100, 200, and 300 mg/kg of body weight/day. Total body weight, stomach tissue, peripheral blood, anti-inflammatory, and pro-inflammatory cytokines were evaluated. Body weight significantly decreased in groups 2 and 3 over four weeks. Neutrophils, lymphocytes, monocytes, and basophils were significantly (p<0.05) elevated in group 4; while hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were significantly decreased (p<0.05). Interleukin-8 (IL-8) level was significantly elevated in groups 3 and 4 versus the control group (p<0.05). Interleukin-6 (IL-6) levels showed a significant (p<0.05) increase in group 4 only. Anti-inflammatory cytokines showed a significant (p<0.05) decrease in all treated groups. The stomach tissues revealed that the extract induced a superficial focal loss of the surface mucous protective epithelium, the atrophy of peptic cells, and a thickening of mucosal connective tissue. The submucosa showed vascular congestion and inflammatory cell infiltration. Severe histological changes were reported in group 4. Using the extract for 20 days led to the elevation of the differential white blood cell (WBC) count as well as the destruction of the gastric mucosal lining at high doses. This could be due to an increase in pro-inflammatory and declining anti-inflammatory cytokines. It is not recommended to use CCT in high doses or for long periods.