The presence of tens of Clostridium botulinum spores per gram of honey can cause infantile botulism. Thermal treatment is insufficient to inactivate these resistant forms. This study explored the effectiveness of supercritical CO2 (scCO2) on its own and combined with lemon (LEO), clove (CLEO), and cinnamon (CEO) essential oils on the inactivation of Clostridium sporogenes (CECT 553) as a surrogate of Clostridium botulinum. In water, the degree of inactivation at 10 MPa after 60 min increased with the increasing temperature, reducing the population by 90% at 40 °C and by 99.7% at 80 °C. In contrast, when applied to honey, scCO2 did not inactivate Clostridium spores satisfactorily at temperatures below 70 °C, which was related to the protective effect of honey. Meanwhile, scCO2 modified with CEO (<0.4% mass) improved the inactivation degree, with a 1.3-log reduction achieved at 60 °C. With this same mixture, a reduction of 3.7 logs was accomplished in a derivative with 70% moisture. Honey was very sensitive to the temperature of the applied CO2. The obtained product could be used as a novel food, food ingredient, cosmetic, or medicine.