Worldwide emission standards are extending their requirements to cover engine operation under extreme ambient conditions and fill the gap between the type-approval and real driving conditions. The new ambient boundaries affect the engine performance and raw emissions as well as the efficiency of the exhaust aftertreatment systems. This study evaluates the impact of high altitude and low ambient temperature on the light-off temperature and conversion efficiency of an oxidation catalyst. The results are compared in a common range of exhaust mass flow and temperature with the baseline sea-level operation at 20 °C. A reduction of CO and HC conversion efficiencies was found at 2500 m and −7 °C, with a relevant increase of the light-off temperature for both of the pollutants. The analysis of the experimental data was complemented with the use of a catalyst model to identify the causes leading to the deterioration of the CO and HC light-off. The use of the model allowed for identifying, for the same exhaust mass flow and temperature, the contributions to the variation of conversion efficiency caused by the change in engine-out emissions and tailpipe pressure, which are, in turn, manifested in the variation of the reactants partial pressure and dwell time as governing parameters.