The increasing accumulation of plastic waste and the widespread presence of its derivatives, micro- and nanoplastics (MNPLs), call for an urgent evaluation of their potential health risks. In the environment, MNPLs coexist with other known hazardous contaminants and, thus, an interesting question arises as to whether MNPLs can act as carriers of such pollutants, modulating their uptake and their harmful effects. In this context, we have examined the interaction and joint effects of two relevant water contaminants: arsenic and polystyrene nanoplastics (PSNPLs), the latter being a model of nanoplastics. Since both agents are persistent pollutants, their potential effects have been evaluated under a chronic exposure scenario and measuring different effect biomarkers involved in the cell transformation process. Mouse embryonic fibroblasts deficient for oxidative DNA damage repair mechanisms, and showing a cell transformation status, were used as a sensitive cell model. Such cells were exposed to PSNPLs, arsenic, and a combination PSNPLs/arsenic for 12 weeks. Interestingly, a physical interaction between both pollutants was demonstrated by using TEM/EDX methodologies. Results also indicate that the continuous co-exposure enhances the DNA damage and the aggressive features of the initially transformed phenotype. Remarkably, co-exposed cells present a higher proportion of spindle-like cells within the population, an increased capacity to grow independently of anchorage, as well as enhanced migrating and invading potential when compared to cells exposed to arsenic or PSNPLs alone. This study highlights the need for further studies exploring the long-term effects of contaminants of emerging concern, such as MNPLs, and the importance of considering the behavior of mixtures as part of the hazard and human risk assessment approaches.