Orange (Citrus sinensis L.) is a common fruit crop widely distributed worldwide with the peel of its fruits representing about 50% of fruit mass. In the current study, orange peel was employed to mediate the synthesis of silver nanoparticles (AgNPs) in a low-cost green approach. Aqueous extracts of suitably-processed peel were prepared using different extraction methods; and their phytochemical profile was identified. Based on phytochemical screening, amount of main phytochemicals, free radical-scavenging ability, reducing power and antioxidant activity, the peel extract prepared by boiling seemed to be the most promising. Thus, major compounds of this extract were identified by gas chromatography-mass spectrometry. Potency of the peel extract to mediate the synthesis of AgNPs was then monitored by visual observation, UV-visible spectroscopy, energy dispersive X-ray analysis, transmission electron microscopy and zetametry. Color change of the reaction mixture to brown and absorption peak at 450 nm indicated AgNPs formation. Characterization of AgNPs revealed spherical shape, size of 30–40 nm, zeta potential of -18.2 mV and yield conversion of 82%. The as-synthesized AgNPs had antioxidant capacity (free radical-scavenging ability, reducing power and antioxidant activity) lower than that of the orange peel extract. However, these biogenic AgNPs had antitumor activity (IC50 of 16 ppm against HCT-116 and 1.6 ppm against HepG2 cell lines) much higher than the peel extract that was completely non-toxic to the considered cell lines.