This article presents a generalized control heuristic to reset supply air temperature set-points for direct-expansion units with capacity modulation and variable airflow and integrates the heuristic into a simplified model predictive control framework that precools building thermal mass through zone temperature set-point adjustments. The resulting control methodology is appropriate for control of medium-sized commercial buildings that employ variable air volume air distribution with direct-expansion units for primary cooling. The heuristic is shown to work well for different direct-expansion systems with different compressor types and fan–duct combinations. To assess the integrated energy savings potential of the heuristic strategy and simplified model predictive control, a simulation platform was developed for a medium-sized commercial building. Simulations were carried out for a 100-day cooling season in different U.S. locations and under different control strategies. The heuristic control provided energy savings of between 5% and 10% relative to conventional control, depending on the system type and location. Approximately 4% additional energy savings was achieved when the heuristic was integrated into a simplified model predictive control having only moderate computational requirements. The cost savings could be significantly greater if time-of-use and demand charges were considered.