<p><i>Citrullus lanatus</i> (watermelon) is widely cultivated for its large, round fruits with juicy pulp. While the pulp is consumed as a dietary staple, the seeds, peels, and rind are often discarded or used as animal feed. However, the protective effect of the seed powder against Ehrlich ascites carcinoma (EAC) has yet to be studied. Thus, the current study aims to evaluate the protective activity of <i>C. lanatus</i> seed powder against EAC-induced cancer growth in a mouse model. The protective activity of <i>C. lanatus</i> seed powder against EAC cells was assessed through multiple parameters, such as cancer cell growth inhibition, inhibition of angiogenesis, survival time extension in tumor-bearing mice, tumor weight reduction, and hematological profile improvement, followed by pretreatment of mice with 5% seed powder in a normal diet for 60 days. Mice pretreated with <i>C. lanatus</i> seed powder demonstrated a 44.77% inhibition of EAC cell growth (<i>p</i> &lt; 0.05), a 35.29 increase in lifespan (<i>p</i> &lt; 0.05), and a significant reduction in tumor weight in EAC-bearing mice in comparison to that of untreated EAC-bearing animals. The seed powder supplement improved hematological parameters such as RBC, WBC, and Hb in tumor-bearing mice. In normal mice, the supplement had no significant adverse effects on hematological and biochemical parameters such as glucose, SGOT, SGPT, LDL, HDL, TG, cholesterol, and creatinine levels, remaining within normal ranges after the treatment period. These findings suggest that <i>C. lanatus</i> seed powder could provide immunity against the growth and proliferation of cancer cells, however, further research is necessary to identify the active compounds and elucidate the underlying mechanisms of its protective anticancer activity.</p>