Preformulation studies are fundamental in pharmaceutical development to ensure dosage form stability and compatibility. We combined in-silico molecular docking with experimental characterization to guide excipient selection and assess drug–excipient compatibility. Acyclovir and trimethoprim were used as model drugs, and lactose monohydrate and microcrystalline cellulose (MCC) as candidate excipients. Docking predicted favorable binding energies for both drugs with MCC and strong interactions in both the drugs and lactose systems because of “Millard”chemical reaction possibility. To validate these predictions, drug–excipient blends were prepared and analyzed by Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and dissolution testing (difference (f1) and similarity (f2) factors). Docking suggested negative binding energy with lactose, indicating drug excipient interactions. FTIR and DSC revealed chemical and thermal interactions in the drug–lactose mixtures, and f1/ f2 analysis showed dissimilar dissolution profiles, indicating incompatibility of the acyclovir–lactose combination. In contrast, acyclovir–MCC and trimethoprim–MCC blends showed no significant incompatibilities. These findings demonstrate that while molecular docking is useful for excipient screening, later experimental testing remains crucial. This proof-of-concept demonstrates that integrating computational docking with experimental validation can effectively predict drug–excipient incompatibilities in preformulation.