<jats:title>Abstract</jats:title><jats:p>Biological activity of <jats:italic>Aconitum</jats:italic> alkaloids may be related to their toxicity rather than to a specific pharmacological action. A Quantitative structure‐activity relationships (QSAR) analysis was performed on the following two groups of alkaloids: compounds with an aroyl/aroyloxy group at R<jats:sub>14</jats:sub> position (yunaconitine, bulleyaconitine, aconitine, beiwutine, nagarine, 3‐acetyl aconitine, and penduline), and compounds with the aroyloxy group at R<jats:sub>4</jats:sub> position (<jats:italic>N</jats:italic>‐deacetyllappaconitine, lappaconitine, ranaconitine, <jats:italic>N</jats:italic>‐deacetylfinaconitine, <jats:italic>N</jats:italic>‐deacetylranaconitine). The <jats:italic>LD</jats:italic><jats:sub>50</jats:sub> (<jats:italic>μ</jats:italic>mol/kg) of the 12 alkaloids were obtained from the literature. <jats:italic>LD</jats:italic><jats:sub>50</jats:sub> was significantly lower in group 1 than in group 2. The steric and core–core repulsion energies were significantly higher in group 1. The total energy and heat of formation and electronic energies were significantly lower in group 1. The reactivity index of N, C1′, C4′ and C6′ were similar between groups. The reactivity index of C2′ was significantly higher and the reactivity index of C3′ and C5′ were significantly lower in group 1. Log P and p<jats:italic>K</jats:italic>a were similar between groups. Molecular weight was significantly higher in group 1. A significant linear relationship was observed between log <jats:italic>LD</jats:italic><jats:sub>50</jats:sub> and either analgesic log <jats:italic>ED</jats:italic><jats:sub>50</jats:sub> or local anesthetic log <jats:italic>ED</jats:italic><jats:sub>50</jats:sub>. The <jats:italic>LD</jats:italic><jats:sub>50</jats:sub>/analgesic <jats:italic>ED</jats:italic><jats:sub>50</jats:sub> obtained from average values was 5.9 for group 1 and 5.0 for group 2. However, the <jats:italic>LD</jats:italic><jats:sub>50</jats:sub>/local anesthetic <jats:italic>ED</jats:italic><jats:sub>50</jats:sub> was 40.4 and 318, respectively. The study supports that the analgesic effects of these alkaloids are secondary to their toxic effects whereas alkaloids from group 2 are susceptible to be further studied as local anesthetic agents.