Cancer, which is characterized by uncontrolled cell growth and division with loss of physiological functions. It is one of the most fatal diseases in the world. For thousands of years, natural treatments, particularly those made from natural products, have been used to cure a variety of diseases, including cancer. Several Arecaceae species have been suggested as potential treatments for a range of cancer types. Arecaceae have a long history of use in folk medicine to treat tumors and a variety of infectious disorders. The green synthesis of silver nanoparticles (SNP) using the total ethanolic extract of Dypsis leptocheilos aerial parts (TEEDL) as a reducing agent was investigated for their cytotoxic activity (using the MTT assay) for the first time. A color change from faint yellow to reddish brown in the first stages of SNP synthesis, indicating the synthesis of nanoparticles. The prepared nanoparticles were also elucidated by using UV-visible spectroscopy, Fourier Transforms infrared spectroscopy (FT-IR), transmission electron microscope (TEM), and Zeta potential. The purified silver nanoparticle preparation demonstrated more promising cytotoxic activity against tested various cell lines than TEEDL. Cell viability by using the MTT assay demonstrated the cytotoxic activity of (TEEDL-based SNPs) against breast cancer cells (MCF-7), liver carcinoma (HepG2), colon carcinoma (HCT-116), and prostate carcinoma (PC-3) cell lines with IC50 = 4.49 ± 0.23, 0.95 ± 0.05, 1.8 ± 0.1, and 2.74 ± 0.52 µg/mL, respectively. To find out which of the secondary metabolites are responsible for this activity, the metabolic profile of TEEDL was investigated. It detected 29 compounds. Finally, a network pharmacology analysis was conducted to find out the annotated genes identified by the major identified flavonoidal compounds. The results identified 145 genes annotated by the 10 major flavonoidal compounds. AKR1B1and CA7 were highly represented genes. Four-gene disease networks were constructed; (gene-breast cancers), (gene-liver cancers), and (gene-colon cancers), and (gene-prostate cancers). KEGG pathway analysis showed the top biological pathways related to all genes were nitrogen metabolism pathway, the VEGF signaling pathway, and EGFR tyrosine kinase inhibitor resistance.