Heavy crude oils constitute the largest reserves; however, their extraction faces several challenges as a result of their high asphaltene content. Reducing the viscosity by physicochemical treatments or chemical transformation on heavy asphaltenes is still a challenge because of matrix complexity. On the other hand, the 1,3-dipolar cycloaddition (1,3-DC) reaction has been used to increase the solubility and rheological properties of graphene and fullerenes, suggesting that 1,3-DC on heavy crude oils can modify directly the chemical structure of titled compounds affecting their aggregation. Starting from Colombian heavy oils and purified asphaltenes, we used a set of chemical modifiers based on long-chain aliphatic and aromatic aldehydes and N-hexylglycine, followed by in situ reactions at several concentrations. Rheological measurements showed a significant reduction on crude oil viscosities up to 98% depending upon the alkyl chain and concentration; furthermore, 1,3-DC reactions between purified asphaltenes and chemical modifiers were followed by nuclear magnetic resonance experiments, which give credence to the viscosity reduction of heavy crude oils based on chemical reactivity.