This study was designed to assess the value of isothermal microcalorimetry (ITMC) as a quality by design (QbD) tool to optimize blending conditions during tablet preparation. Powder mixtures that contain microcrystalline cellulose (MCC), dibasic calcium phosphate dihydrate (DCPD), and prednisone were prepared as 1:1:1 ratios using different blending sequences. ITMC was used to monitor the thermal activity of the powder mixtures before and after each blending process. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were performed on all final powder mixtures. Final powder mixtures were used to prepare tablets with 10 mg prednisone content, and dissolution tests were performed on all tablet formulations. Using ITMC, it was observed that the powder mixtures had different thermal activity depending on the blending sequences of the ingredients. All mixtures prepared by mixing prednisone with DCPD in the first stage were associated with relatively fast and significant heat exchange. In contrast, mixing prednisone with MCC in the first step resulted in slower heat exchange. Powder mixture with high thermal activity showed extra DSC peaks, and their dissolution was generally slower compared to the other tablets. Blending is considered as a critical parameter in tablet preparation. This study showed that ITMC is a simple and efficient tool to monitor solid-state reactions between excipients and prednisone depending on blending sequences. ITMC has the potential to be used in QbD approaches to optimize blending parameters for prednisone tablets.