Different supporting procedures were followed to alter the nanoparticle-support interactions (NPSI) in two Co3O4/Al2O3 catalysts, prepared using the reverse micelle technique. The catalysts were tested in the dry preferential oxidation of carbon monoxide (CO-PrOx) while monitoring their phase stability using four complementary in situ techniques, viz. magnet-based characterisation, PXRD, combined XAS/DRIFTS as well as quasi in situ XPS, respectively. The catalyst with weak NPSI achieved higher CO2 yields and selectivities at temperatures below 225 °C compared to the sample with strong NPSI. However, relatively high degrees of reduction of Co3O4 to metallic Co were reached between 250 and 350 °C for the same catalyst. The presence of metallic Co led to the undesired formation of CH4, reaching a yield of over 90% above 300 °C. The catalyst with strong NPSI formed very low amounts of metallic Co (less than 1%) and low CH4 (yield of up to 20%) even at 350 °C. When the temperature was decreased from 350 to 50 °C under the reaction gas, both catalysts were slightly re-oxidised and gradually re-gained their CO oxidation activity while the formation of CH4 diminished. The present study, for the first time, shows a strong relationship between catalyst performance (i.e., activity and selectivity) and phase stability, both of which are affected by the strength of the NPSI. When using a metal oxide as the active CO-PrOx catalyst, it is important for it to have significant reduction resistance to avoid the formation of undesired products, e.g., CH4. However, the metal oxide should also be reducible (especially on the surface) to allow for a complete conversion of CO to CO2 via the Mars-van Krevelen mechanism.