Background Fasting C-peptide (FCP) has been shown to play an important role in the pathophysiology of mood disorders including depression and schizophrenia, but it is unknown whether it also predicts post-stroke depression (PSD). This study examined the association between FCP and PSD at 6 months after acute ischemic-stroke onset among Chinese subjects. Methods A total of 656 stroke patients were consecutively recruited from three hospitals of Wuhan city, Hubei province. Clinical and laboratory data were collected on admission. PSD status was evaluated by DSM-V criteria and 17-item Hamilton Rating Scale for Depression (HAMD-17) at 6 months after acute ischemic stroke. The chi 2-test, Mann-Whitney U-test, and t-test were used to check for statistical significance. Multivariate logistic regression model was used to explore independent predictor of PSD. Results In the univariate analysis, significant differences were found between the PSD and non-PSD groups in terms of FCP level (p = 0.009). After multivariate adjustments, FCP remained a significant independent predictor of PSD, with an adjusted odds ratio of 1.179 (95%CI: 1.040-1.337, p = 0.010). Conclusions Higher FCP levels on admission were found to be associated with PSD at 6 months after acute ischemic-stroke onset. For stroke patients, doctors should pay attention to the baseline FCP for screening high-risk PSD in clinical practice.