Brucine (BRU) as a natural alkaloid has antitumor, anti-inflammatory and anti-proliferation activity However; its clinical application is limited due to its low water solubility. The aim of this study was to increase the therapeutic efficacy of BRU using PEGylated niosomal as nanocarrier. Here BRU loaded niosomes using different surfactants (Brij 52, Span 60 and Poloxamer 184) with and without PEG-DSPE were prepared. Niosomes were fabricated with particle size not exceeding 311 nm and entrapment ranged between 53 and 64%. Total serum protein adsorbed was ranged from 18.2 ± 3.7 up to 47.5 ± 3.2 μg/μl total lipids. In vitro drug release showed no sig- nificant difference for PEGylated niosomes over 24 h with and without serum incubation. In vitro cytotoxicity assay revealed that PEGylated niosome prepared with span 60 has considerable anti-cancer activity against MDA- MB-231 cell line comparable with blank niosome, free BRU and naked counterpart. Eventually, PEGylated niosomal formulation demonstrated the lowest tumor volume (732.42 mm3) and enhanced survival time (57 days). Based on the obtained results, loading the niosomes with BRU and coating them with PEG enhanced their efficacy and selectivity toward cancer cells, presenting a promising drug delivery system for targeting drug to cancer tissue.