Through molecular dynamics (MD) simulations with ReaxFF potential, the effects of chemical contaminants on the mechano-chemical properties and tribological performance of perfluoropolyether (PFPE) lubricants were investigated. For the two types of contaminants, i.e., silicon dioxide (SiO2) nanoparticles and water (H2O), their molecular interactions with the two different PFPE lubricants, i.e., Ztetraol and ZTMD, were evaluated at the two different temperatures, i.e., 300 K and 700 K. Contaminants were adsorbed onto the PFPE lubricants at a controlled temperature. Then, air shear simulations were conducted to examine the mechano-chemical behaviors of the contaminated lubricants. Sliding contact simulations were performed to further investigate the tribological performance of the contaminated lubricants, from which the resulting friction and surface contamination were quantified. Lastly, chemical reactions between PFPE lubricants and contaminants were studied to investigate the degradation of PFPE lubricants. It was observed that SiO2 nanoparticles stiffened the PFPE lubricant, which decreased its shear displacement and increased friction. In the case of the H2O contaminant, it weakened and decreased the PFPE lubricant’s viscosity, increasing its shear displacement and lowering friction. However, the decreased viscosity by H2O contaminants can weaken the lubricity of the PFPE lubricant, leading to a higher chance of direct solid-to-solid contact under high contact force conditions.