Histon deacetylase 4 (HDAC4) modulates memory and cognitive impairment, but its association with post-stroke cognitive impairment (PSCI) is unclear. This study aimed to investigate the potential of HDAC4 for predicting PSCI risk. Sixty-nine PSCI patients and 70 control post-stroke (CPS) patients were enrolled in this case-control study. In all stroke patients, HDAC4 in peripheral blood mononuclear cells was detected by quantitative polymerase chain reaction; T-helper 17 (Th17) cells were detected by flow cytometry, and interleukin-17A was detected by enzyme-linked immunosorbent assay. HDAC4 was reduced in PSCI patients compared with CPS patients (P = 0.001). In total stroke patients, HDAC4 showed negative linkages with age (P = 0.003), history of diabetes (P = 0.012), stroke recurrence (P = 0.001), Th17 cells (P = 0.027), and interleukin-17A (P = 0.002). Additionally, multivariate logistic regression analysis revealed that HDAC4 (per unit) [odds ratio (OR) = 0.438, P = 0.024] was independently associated with a lower PSCI risk, but age (per unit) (OR = 1.061, P = 0.016) and multifocal disease (yes vs. no) (OR = 2.490, P = 0.014) were independently associated with a higher PSCI risk. By receiver operator characteristic curves, HDAC4 had an acceptable value for predicting PSCI risk [area under the curve (AUC) = 0.656, 95% confidence interval = 0.566-0.746]. The combination of HDAC4, age, and multifocal disease showed a good value for predicting PSCI risk (AUC = 0.728, 95% confidence interval = 0.644-0.811). HDAC4 may serve as a potential biomarker for predicting PSCI risk, which could facilitate the early screening and prevention of PSCI, thus promoting the management of stroke.