Caffeine, theophylline, and aminophylline are important methyl-substituted xanthines and are widely used in clinics. In this work, the thermodynamic characteristics of the three drugs were studied by adiabatic calorimetry, thermogravimetric analysis (TG) and differential scanning calorimetry (DSC). The low temperature molar heat capacities of caffeine (in the β crystal form), theophylline and aminophylline were measured by heating the system from 80 to 370 K using an adiabatic calorimeter. The results indicate that the molar heat capacity of aminophylline is the largest while that of theophylline is the smallest. The experimental molar heat capacities of the three drugs were fitted to a polynomial of C_{p, m} *vs* the reduced temperature (t) by means of the least fitting square method from 80 to 370 K. Their molar heat capacities at 298.15 K were calculated to be 226.49 J·K^{-1}·mol^{-1} (for caffeine), 218.13 J·K^{-1}·mol^{-1} (for theophylline), and 554.78 J·K^{-1}·mol^{-1} (for aminophylline) using the polynomial C_{p, m}-t. Thermodynamic parameters (such as enthalpies and entropies relative to 298.15 K) were calculated for these drugs based on the polynomial C_{p, m}-t. The results of thermal analysis show that the order of thermal stability for these drugs is aminophylline＜caffeine＜theophylline. The temperatures, enthalpies and entropies of the phase transitions for caffeine and theophylline were obtained by DSC. The stabilities of the molecular structures for caffeine and theophylline were calculated by a first-principles calculation based on density functional theory. The results imply that the stability of the caffeine molecule is lower than that of theophylline and this is in good agreement with the experimental results.