Heme-copper oxidases (HCOs) couple the chemical energy released in reduction of oxygen to water, the final step of the respiratory chain, to the active proton translocation across the membrane, thus contributing to the establishment of a proton gradient, which is essential for ATP synthesis. Cbb3 (or C-type) cytochrome c oxidases are a highly divergent group and the least studied members of the HCO superfamily. They exhibit unique structural and functional features, and have an essential role in metabolism of clinically relevant human pathogens. The functioning mechanism of cbb3 oxidases, namely the proton transfer/pumping mechanism via a single proton channel, is still poorly understood. In this work we use a combination of computational tools to get atomic-level insights into the water dynamics and proton translocation in cbb3 oxidase. Recently we described the proton transfer pathways for the “chemical” and “pumped” protons, and proposed a redox-driven pumping mechanism (Carvalheda 2017 BBA-Bioenerg. 1858 396). Here we report the impact of redox changes in the binuclear centre on the proton pathways and protonation equilibria of key residues. Our results contribute to a better understanding of cbb3 mechanism and provide ideas for further experimental and computational studies.