Cilomilast is an oral phosphodiesterase-4 (PDE4) inhibitor recommended for treating COPD. However, its side effects and low therapeutic index remain an unresolved problem in clinical practice. This study aimed to evaluate the effects of cilomilast on the spleen and thymus tissues of rats. For experimental studies, 24 male Sprague-Dawley rats weighing 200-220g were randomly divided into three experimental groups: The procedures were repeated for 7 days for the control, sham, and cilomilast groups. Blood and tissue samples were collected from the rats under anesthesia on day 8 of the experiment for analysis. p<0.05 at a 95% confidence level was considered to indicate statistical significance. Severe tissue damage in the thymus and spleen was observed in the cilomilast group. In the thymus and spleen tissues of the control and sham groups, CD4⁺ and CD8⁺ cell immunopositivity were more intense, while the density of these cells was significantly reduced in the cilomilast group. In addition, glutathione (GSH) levels decreased, and nitric oxide levels increased in both tissues of the cilomilast group. However, in-silico results showed that the decrease in GSH levels is due to the enzymes γ-glutamylcysteine synthase and glutathione synthase, which act as catalysts in the two-step GSH biosynthesis mechanism. Suppression of the immune system targets both harmful and compensatory pathways so that both beneficial mechanisms and pathological changes can be blocked. To eliminate these cilomilast-induced side effects and enable more effective clinical application, it may be recommended to develop formulations such as lipid-based inhaled forms or nano-drug delivery systems including dendrimers, reverse micelle systems, polymeric or lipid-based carriers as an alternative to conventional application.