Chemical control of the maize weevil (Sitophilus zeamais) has been ineffective and presents serious collateral damage. Among plant-derived insecticides, essential oils (EOs) are suitable candidates to control this stored products pest. In this work, the insecticidal activities of 45 natural EOs against S. zeamais adults were screened, and the most promising ones (24 EOs) were characterized by GC–MS. The repellent and toxic effects (contact and fumigant) of these 24 EOs were determined, and by a cluster analysis they were classified into two groups considering its fumigant activity and contact toxicity. For the EOs with the highest fumigant potential (14 oils) and their main active constituents (17 compounds), lethal concentrations were determined. The most active EOs were those obtained from L. stoechas and L. alba, with LC₅₀ values of 303.4 and 254.1 µL/L air and characterized by a high content of monoterpenes. Regarding the major compounds, the oxygenated monoterpenes R-(+)-pulegone (LC₅₀ = 0.580 mg/L air), S-(-)-pulegone (LC₅₀ = 0.971 mg/L air) and R-(-)-carvone (LC₅₀ = 1.423 mg/L air) were the most active, as few variations in their concentrations significantly increased insect mortality.

Sitophilus zeamais, a major pest of stored grains, causes significant post-harvest losses and challenges effective control. While synthetic insecticides pose risks of resistance and toxicity, essential oils (EOs) offer a safer alternative. However, the insecticidal potential of their individual volatile constituents (VCs) remains largely unexplored. This study evaluated the insecticidal activity of 51 EO-derived volatile compounds (VCs) against S. zeamais, identifying the most toxic ones, optimizing 15 synergistic mixtures, and assessing their effects on key insect enzymes. A structure–activity relationship (SAR) analysis determined functional groups associated with insecticidal activity, while a cluster analysis pre-selected 29 ternary mixtures, later refined using response surface methodology (RSM). Additionally, enzymatic assays explored their impact on detoxification and nervous system enzymes, providing insights into potential mechanisms of action. Among the 51 VCs tested, 37 exhibited significant toxicity, with 11 acting as fumigants and 13 displaying contact toxicity. Monocyclic monoterpenoids with ketone or alcohol functional groups and exocyclic unsaturation demonstrated the highest insecticidal activity via both exposure routes. Notably, pulegone enantiomers were particularly effective (LC₅₀ < 0.1 mg/L, LD₅₀ < 7.5 µg/adult). Among the optimized mixtures, 10 displayed strong insecticidal effects, 8 were active through both routes, and 5 exhibited synergistic fumigant interactions. The most effective formulations were M2 (R-pulegone + S-pulegone + S-carvone, LC₅₀ 0.48 mg/L) and M20 (isopulegone + δ-3-carene, LC₅₀ 2.06 mg/L), showing the strongest fumigant and synergistic effects, respectively. Enzymatic assays revealed that while some compounds mildly inhibited GST and CAT, others, such as δ-3-carene (IC₅₀ 0.19 mg/L), significantly inhibited AChE. Five mixtures exhibited synergistic neurotoxicity, with M20 (IC₅₀ 0.61 mg/L) and M12 (IC₅₀ 0.81 mg/L) emerging as the most potent AChE inhibitors. These findings highlight the potential of plant-derived volatile compounds as bioinsecticides, leveraging synergistic interactions to enhance efficacy, disrupt enzymatic pathways, and mitigate resistance.