This study aimed to comparatively optimize and evaluate the quality characteristics of Washington Navel orange slices using vacuum microwave drying (VMD) and conventional hot air drying (HAD) systems. Response Surface Methodology based on the Box–Behnken design was applied to both systems. For the models developed in the VMD system, the coefficient of determination (R²) was found to be in the range of 0.96–0.97, and the optimum conditions were determined as 4 kW power, 60 °C temperature, and 2 mm slice thickness. For HAD, the optimum conditions were determined as 78 °C temperature, 1.57 m/s air velocity, of 2.3 mm slice thickness. VMD showed superior performance compared to hot air drying in terms of total phenolic preservation, retention of bioactive compounds, and rehydration capacity. Hydroxymethylfurfural (HMF) formation was higher during hot-air drying. The effective moisture diffusivity (D_eff) was significantly higher in VMD (8.38 × 10⁻¹⁰ m²/s) than in HAD (1.49 × 10⁻¹⁰ m²/s), indicating enhanced internal moisture transport under vacuum microwave conditions. The results revealed that VMD is an efficient technology for producing high-quality dried citrus products with improved bioactive retention and reduced processing time.