To investigate the effect of the TGF-β1/Smad3 signaling pathway on cognitive dysfunction from obstructive sleep apnea syndrome (OSAS) and the regulation of TGF-β1. Methods: Chronic intermittent hypoxia (CIH) was used to construct the OSAS model. Disitertid (P144) was selected for TGF-β1 inhibition. Forty-two adult male SD rats were randomly divided into the following 7 groups with 6 rats in each: normal control (N) group, CIH 1 week (1W) group, CIH 2W group, CIH 3W group, CIH 4W group, CIH 4W+ P144 group, and CIH 4W+DMSO group. Rats in each group were subjected to hypoxia for the corresponding duration of time. CIH 4W+P144 group rats and CIH 4W+DMSO group rats were intraperitoneally injected with P144 (70 μg/kg) and DMSO (1 mL/kg) respectively, once every other day, before modeling. After model establishment, the Morris water maze (MWM) was used to detect the learning and memory ability of the rats; Nissl staining was used to observe the hippocampal CA1 and CA3 neurons for pathological changes; and Western blotting was used to quantitatively detect TGF-β1, tSmad3, and pSmad3 proteins in the hippocampus of rats in each group. Results: OSAS model rats displayed daytime sleepiness and irritability and compared with in reoxygenation time, the mean oxygen saturation decreased by > 4% in hypoxia time (P<0.05), which indicating successful model establishment. For rats in the CIH 2W, 3W, and 4W groups compared to those in the N group, escape latency was prolonged, and the number of platform crossings was decreased (all P<0.05) in MWM. Compared to rats in the CIH 4W+DMSO group, rats in the 4W+P144 showed a decreased escape latency and increased platform crossings (all P<0.05). Nissl staining in OSAS model rats showed nerve cell structural damage, reduced numbers of Nissl bodies, lightly stained cytoplasm, and the eventual disappearance of Nissl bodies. The CIH 4W+P144 group showed a large number of Nissl bodies and relatively complete structure, with the degree of cell damage being relatively light. Compared to that in N group rats, the expression of TGF-β1 and pSmad3 in the CIH 1W, 2W, 3W, and 4W rats was increased (all P<0.05). The expression of TGF-β1 and pSmad3 protein decreased in the 4W+P144 group compared with the 4W+DMSO group (all P<0.05). Conclusion: The TGF-β1/Smad3 signaling pathway is activated in cognitive dysfunction in OSAS rats. The spatial learning and memory ability of cognitively impaired OSAS rats is improved to some extent after specific inhibition of TGF-β1.