Asphaltenes and paraffin are considered the molecules present in heavy crude oils that tend to form aggregates that cause high viscosity values. Understanding the molecular interactions occurring in such aggregation phenomena is essential to apply flow enhancers that effectively reduce viscosity and positively impact power requirements in production fields. In this sense, this work develops a methodology that involves the molecular interaction energies determined by computational chemistry in the obtention of a semiempirical model to predict viscosity reduction. The model was developed based on heavy crude oil (8.88 °API, saturated fraction 33.23%, asphaltene fraction 26.46%, and 156.853 mPa s at 30 °C) dosed with a biodiesel-based flow enhancer which active principle is a fatty acid ester. The model predicted a 50% reduction of viscosity and, according to transport phenomena equations, pressure drop and the pumping power required for transport are also decreased by 50%. The semiempirical results were contrasted against field results, where the reduction expected of pressure drop was obtained. Such an outcome confirms that the assumed asphaltene-ester interaction in the computational study governs the flow enhancer activity in avoiding aggregation performed by asphaltene and paraffin molecules.