Laccases and multicopper oxidases (MCOs) oxidize a wide range of organic compounds while reducing O2 to water, enabling numerous biotechnological applications. It is still unknown how O2 reaches the internalized catalytic center of MCOs where it gets reduced, despite a proposed channel inferred from X-ray crystallography structures. Herein, an alternative new pathway is found through the use of a combination of free energy calculations (implicit ligand sampling), landscape analysis, and Markov modeling. The reported pathway is shown to be the one mostly contributing to O2 reaching the catalytic center. This pathway is considered in light of the whole MCO family, and a relation to the protonation state of a structurally conserved acidic residue right above the center is advanced.