The study targeted towards drying of cantaloupe slices with various thicknesses in a microwave dryer. The experiments were carried out at three microwave powers of 180, 360, and 540 W and three thicknesses of 2, 4, and 6 mm for cantaloupe drying, and the weight variations were determined. Artificial neural networks (ANN) and adaptive neuro-fuzzy inference systems (ANFIS) were exploited to investigate energy and exergy indices of cantaloupe drying using various afore-mentioned input parameters. The results indicated that a rise in microwave power and a decline in sample thickness can significantly decrease the specific energy consumption (SEC), energy loss, exergy loss, and improvement potential (probability level of 5%). The mean SEC, energy efficiency, energy loss, thermal efficiency, dryer efficiency, exergy efficiency, exergy loss, improvement potential, and sustainability index ranged in 10.48–25.92 MJ/kg water, 16.11–47.24%, 2.65–11.24 MJ/kg water, 7.02–36.46%, 12.36–42.70%, 11.25–38.89%, 3–12.2 MJ/kg water, 1.88–10.83 MJ/kg water, and 1.12–1.63, respectively. Based on the results, the use of higher microwave powers for drying thinner samples can improve the thermodynamic performance of the process. The ANFIS model offers a more accurate forecast of energy and exergy indices of cantaloupe drying compare to ANN model.