Quantum dots (QDs) are luminescent nanoparticles (NPs) with promising potential in numerous medical applications, but there remain persistent human health and safety concerns. Although the cytotoxic effects of QDs have been extensively investigated, their genotoxic effects remain under-explored. This study scrutinized the cyto- and genotoxic effects of QDs with a Cadmium selenide/Zinc sulfide (CdSe/ZnS) core/shell, and suggests comprehensive guidelines for the application of QDs in cancer therapy. QDs were used to treat A549 cells in the presence and absence of ultraviolet A/B (UVA/UVB) irradiation. QD-induced cell death was evaluated by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), apoptosis, and lactate dehydrogenase (LDH) assays, as well as by real-time PCR analysis of differential mRNA levels of genes, such as ataxia telangiectasia mutated (ATM), p53, and caspase-9, involved in apoptosis. The genotoxic effect of CdSe/ZnS QDs was measured in human cancer cells, for the first time, by comet and micronucleus assays. Treatment with CdSe/ZnS QDs and UVB irradiation resulted in the most severe extent of cell death, indicating strong induction of phototoxicity by CdSe/ZnS QDs in the presence of UVB. Both apoptotic and necrotic cell death were observed upon QDs and UVB combined treatment. The induction of Olive tail moments and micronuclei formation was also most significant when CdSe/ZnS QDs and UVB irradiation were combined. Our results on the genotoxic effect and mechanistic details of CdSe/ZnS QD-induced cell death suggest that UVB irradiation is the most effective method for increasing the potency of QDs during photodynamic cancer therapy.