Ciprofloxacin (CIP) is a broad-spectrum antibiotic found within μg/L concentration range in the aquatic environment. It is a known contributor of umuC induction in hospital wastewater samples. CIP can undergo photolysis to result in many transformation products (TPs) of mostly unknown toxicity. The aims of this study were to determine the genotoxicity of the UV mixtures and to understand the possible genotoxic role of the stable TPs. As such, CIP and its UV-irradiated mixtures were investigated in a battery of genotoxicity and cytotoxicity in vitro assays. The combination index (CI) analysis of residual CIP in the irradiated mixtures was performed for the umu assay. Further, Quantitative Structure-Activity Relationships (QSARs) predicted selected genotoxicity endpoints of the identified TPs. CIP achieved primary elimination after 128 min of irradiation but was not completely mineralized. Nine photo-TPs were identified. The irradiated mixtures were neither mutagenic in the Ames test nor genotoxic in the in vitro micronucleus (MN) test. Like CIP, the irradiated mixtures were umuC inducing. The CI analysis revealed that the irradiated mixtures and the corresponding CIP concentration in the mixtures shared similar umuC potentials. QSAR predictions suggested that the TPs may be capable of inducing chromosome aberration, MN in vivo, bacterial mutation and mammalian mutation. However, the experimental testing for a few genotoxic endpoints did not show significant genotoxic activity for the TPs present as a component of the whole mixture analysis and therefore, further genotoxic endpoints may need to be investigated to fully confirm this.