© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.For drying of heat-sensitive crops at low temperature and humidity, heat pump drying (HPD) could be a useful option. The aim of this study was to investigate the effect of HDP process conditions on total phenolic content (TPC), antioxidant activity (AA) and their in-vitro bioaccessibility of the melon slices and to optimize HPD conditions to obtain dried product with high bioactive properties. Drying air temperature (35–45 °C), air velocity (5–9 m/s) and slice thickness (0.5–1 mm) were selected as variables for Box-Behnken experimental design. Depending on the stability of the phenolics, physical changes of the matrix, and the HPD conditions, both incremental (2–114.39%) and decremental (5–47%) effects of drying were observed for AA and TPC of the melon slices. After in vitro digestion, dried melon slice was found to contain higher amounts of bioaccessible total phenolics (up to 165%) and AA measured by DPPH assay (up to 188.19%) compared to fresh melon slices, on the other hand bioaccessibility of AA by CUPRAC and FRAP assays after digestion decreased (up to 63%) by drying process. The relation between the responses (AA, TPC and their in-vitro bioaccessibility) and the variables were best fitted to quadratic, reduced quadratic and reduced cubic models with high R2 values by response surface methodology. The optimal condition for all responses with composite desirability of 0.777 was: 35 °C drying air temperature, 0.5 m/s drying air velocity and 9 mm slice thickness. Melon slices dried by HPD could be accepted as an innovative snack for health-conscious consumers.