Atriplex halimus has demonstrated antiproliferative properties, yet its effects on Ehrlich solid tumor (EST) remain unexplored. This research sought to investigate the therapeutic effect of A. halimus ethanolic extract on EST in mice and elucidate its underlying mechanisms of action. To achieve our goal, Swiss albino mice were used to induce EST and divided into four groups negative control, untreated EST, EST treated with 180 mg/kg A. halimus extract, and EST treated with 360 mg/kg A. halimus extract. Gene expression, protein levels, and DNA damage in tumor tissues were assessed using qRT-PCR, western blot, and comet assay. Our results showed significant tumor size reduction in EST in mice treated with both low and high doses of A. halimus crude extract compared to untreated EST mice. Real-time PCR and protein expression analyses revealed that A. halimus extract activated apoptotic mechanisms, leading to increase expression of p53, Caspase 3, and cdc2 while downregulating Bcl-2 at the mRNA level in treated EST in mice. Furthermore, the comet assay demonstrated the genotoxic potential of A. halimus on solid tumor cells.Our findings show that A. halimus may be a promising natural source of anti-proliferative agent for cancer. However, further clinical trials are necessary to prove its effectiveness and safety for therapeutic use. This research provides valuable insights into the molecular mechanisms underlying the antitumor effects of A. halimus and highlights its potential in cancer treatment strategies.