The purpose of this study was to investigate the effects of theophylline and methylprednisolone on the mechanical response and histopathology of hemidiaphragm muscle in rats. In the current study, we aimed to investigate the effects of theophylline and methylprednisolone, which are frequently used in clinics and which have different effects on the respiratory system and on the biomechanics and histopathology of the diaphragm muscle. The study included four groups of rats. Group T received 1 mg/kg of intraperitoneal theophylline, group M received 2 mg/kg of intraperitoneal methylprednisolone, group TM received 1 mg/kg of intraperitoneal theophylline plus 2 mg/kg of intraperitoneal methylprednisolone, and group K received of 1 mL intraperitoneal isotonic solution (of 0.9 % NaCl). The medications were continued for 7 days in each group. The rats underwent cervical dislocation under anesthesia on the eighth day, and their diaphragm samples were extracted. The left hemidiaphragm was used for the investigation of biomechanical parameters, and the right hemidiaphragm was used for the histopathological evaluation. It was observed that the medication administered in group T increased the contraction strength and duration compared with that in group M. Additionally, the duration of semi-relaxation was prolonged in group T compared with group M. The highest contraction strength and the longest contraction period among all of the groups were observed in group TM. It was concluded that the combined use of theophylline and methylprednisolone had positive effects on the contraction strength and the durations of contraction and semi-relaxation of the diaphragm muscle. In addition, both drugs had synergistic effects on each other.