Laser cutting has experienced a sharp development in recent years due to the advantages it implies in industrial production, the most important being: great diversity of processed materials, reduced cutting time, low processing cost, small percentage of removed material, and low impact on the natural environment. The problem of energy has become acute in the last year, so a new direction of research has taken shape, consisting of the optimization of the high energy consumptions involved in laser cutting. The objective of this research is to develop a computational and experimental model to estimate the melting efficiency. Additionally, the research seeks to establish some mathematical relationships that describe the law of variation of the melting efficiency depending on the input parameters in the CO2 laser cutting. The experimental determinations were carried out on Hardox 400 steel plates of 8 mm thickness. The input parameters were laser power, assist gas pressure, and cutting speed. The experimental data were statistically processed, and the results were verified with the Lagrange interpolation method. It was found that the maximum melting efficiency is influenced mainly by laser power (F = 3.06; p = 0.049), followed by speed and pressure. The results obtained show that the melting efficiency varies in the range (13.6–20.68) mm3/KJ. The maximum value of the melting efficiency (20 J/mm3) was obtained when the laser power was 5100 W, the cutting speed 1900 mm/min, and the gas pressure 0.5 bar, and the minimum efficiency under conditions of speed setting at 1700 mm/min and laser power of 5000 W. Linear and quadratic regression models were established to estimate the global mean efficiency according to two independent variables that act at the same time. The established calculation relationships contribute to the improvement of the literature and constitute a tool for practical applications. The results obtained allow the modeling of cutting parameters and the optimization of production costs in industrial processes that use laser cutting.