Systems of amylose with nimesulide or tretinoin are prepared and characterized in order to evaluate their in vitro release behavior. X‐ray diffraction (XRD) data of the amylose systems containing drug molecules reveal patterns characteristic of the V‐type of complexed amylose. Nevertheless, they cannot be unequivocally assigned to complexed amylose since both drugs exhibit XRD reflections at similar 2‐theta angles. Raman scattering and differential scanning calorimetry thermal analysis provide evidence suggesting that tretinoin is more likely to form molecular inclusion complexes than nimesulide. The drug–amylose interaction is also assessed by means of optical microscopy, confocal laser scanning microscopy, and scanning electron microscopy. The results reveal that the drug molecules are effectively entrapped in the amylose matrix, probably inside or between the amylose helices. Acidic and enzymatic tests allow the quantification of the drug molecules released from the matrix of the amylose systems with tretinoin or nimesulide. In the simulated intestinal fluid, the drug release of the samples reached up to ≈52% for tretinoin and ≈39% for nimesulide systems. Overall, the results show that the molecular interaction of amylose, with tretinoin appears to be more promising for efficient complexation than with nimesulide.