This study aimed at targeting hepatic cancer stem cells (CSCs) with quercetin (Q) or kaempferol (K) loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs) decorated with CD133 antibody. For this purpose, the formulated Q NPs and K NPs and their free forms were evaluated for their cytotoxic potential, apoptotic activity, and anti-migratory effect against CD133(+) CSCs isolated from the Huh7 cell line. Moreover, their influence on the hepatic CSCs-relevant molecular pathways was evaluated through analyzing several related gene expression levels. Interestingly, the in vitro study revealed that the Q NPs and K NPs and their free forms exhibit significant cytotoxic potential against CSCs isolated from the Huh7 cell line. The flow cytometric analysis revealed that Q NPs recorded the highest induction of apoptosis (77.8%) relative to the control (1.8%). The migration of hepatic CSCs is restrained by treatment with the suggested NPs and their free forms, but the most pronounced effect was observed after treatment with Q NPs. Both Q NPs and K NPs triggered significant down-regulation in the expression level of ABCG2, survivin, vimentin, cyclin D1, c-Myc, MMP-7, and VEGF genes in hepatic CSCs. The treatment with Q NPs motivated significant up-regulation in the expression level of the P53 gene in hepatic CSCs. Conclusively, the obtained results shed light on the success of Q NPs and K NPs modified with CD133 antibody on their surfaces in targeting hepatic CSCs. This effect was evidenced by their ability to significantly induce apoptosis, inhibit metastasis, reverse drug resistance, and interfere with CSC-associated signaling pathways.