MXenes have gained significant attention, particularly Ti3C2Tz, as materials with favorable properties for energy storage and conversion applications. The overwhelming majority of electrochemical durability studies are based on durability in the hydrogen evolution window, well below the reversible hydrogen electrode where degradation via electrochemical oxidation is less relevant. Consequently, few strategies have been put forward to protect Ti3C2Tz at higher potentials and widen their applicability to electrochemical systems. Here, the electrochemical degradation of pristine Ti3C2Tz and tantalum (Ta)-substituted (Ti0.95Ta0.05)3C2Tz is reported. X-ray photoelectron spectroscopy and electron microscopy revealed that pristine and Ta-doped MXene went through entirely different degradation mechanisms, and that these mechanisms are driven by electrochemical, rather than chemical effects. Density functional theory is used to explain the role of Ta doping with respect to the binding of oxygen and the formation of metal oxide phases. The influence of the degradation mechanism is observed by accelerated stress tests and anode reversal tests on a polymer electrolyte membrane fuel cell. Therefore, the substitution of titanium (Ti) with other oxyphilic metals in Ti3C2Tz may be an effective route to improve the durability of the otherwise fragile MXene phase.