Objective To study the correlation between serum cysteine (Hcy), S100B protein and the severity of cognitive impairment in patients with bipolar disorder. Methods A retrospective analysis of 120 patients with bipolar disorder admitted to the Third People's Hospital of Maoming City from January 2019 to February 2021 According to whether they had cognitive impairment, the patients were divided into control group [Montreal Cognitive Assessment Scale score (MoCA) ≥ 26, 30 cases], mild group (21≤MOCA＜26, 60 cases) and severe group (MoCA score＜21, 30 cases). The scores of Hasegawa Dementia Scale (HDS) and mini mental state examination (MMSE) were analyzed, the serum HCY and S100B proteins of the three groups were detected, and the correlation between cognitive impairment and the above indexes was analyzed. Results After treatment, the serum Hcy and S100B protein of the three groups were significantly lower than those before treatment (P＜0.05). There were significant differences in serum Hcy and S100 protein levels between the three groups before and after treatment (P＜ 0.05); The serum Hcy of the three groups after treatment was significantly higher than that before treatment, and the S100B protein was significantly lower than that before treatment (P＜0.05). There were significant differences in serum Hcy and S100 protein levels between the three groups before and after treatment (P＜0.05); There was a significant negative correlation between MOCA scores and serum Hcy and S100B protein levels before and after treatment (P＜0.05). Conclusion before and after treatment, serum Hcy and S100B protein will change significantly with the same score as HDS and MMSE, and there are significant differences in patients with different degrees of cognitive impairment. Therefore, it is considered that serum Hcy and S100B proteins are related to patients' cognitive impairment, which is expected to be the basis for judging the condition and cognitive function.