Clay minerals have different negative effects on the froth flotation process such as low adsorption of collectors on valuable minerals, increased pulp viscosity, and the reduction in recovery and grade concentrates of copper sulfides. This study aims to evaluate the use of polystyrene-based nanoparticles (NPs) for the froth flotation of chalcopyrite and their ability to mitigate the negative effect of montmorillonite on the recovery of this sulfide. The experimental stage consisted of preparing a type of polystyrene-based nanoparticle (St-CTAB-VI), which was analyzed by dynamic night scattering (DLS) to establish its hydrodynamic size. Then, the effect of NPs on chalcopyrite's angle's in the presence and absence of montmorillonite (15%) was evaluated and compared with the contact angle achieved using potassium amyl xanthate (PAX) and a mixture of PAX and NPs. In addition, zeta potential measurements were carried out to investigate the interactions between the chalcopyrite and the montmorillonite or the NPs under fixed concentrations and microflotation tests were performed employing different times to evaluate the chalcopyrite recovery in the presence of montmorillonite, using NPs and mixtures with PAX. Finally, turbidity analysis as a function of time was performed to evaluate the occurrence of sedimentation and flocculation phenomena in suspensions of 15% montmorillonite in the presence and absence of chalcopyrite, nanoparticles, and mixtures of NPs and PAX. The results indicated that the mixture of NPs and PAX contributed to increasing the contact angle of chalcopyrite in the presence of montmorillonite. This can be associated with the presence of molecular and nanometric collectors that generated a higher hydrophobicity on the chalcopyrite particles, contributing to reducing the presence of clay minerals on the mineral surface. In addition, the mixture of NPs and PAX promoted the generation of nanoparticles on the sulfide mineral surface, which helps to detach the slime and facilitate the bubble/mineral attachment step during flotation.