Background: Depression is a frequent mood disorder in stroke patient. Our aim was to determine irisin levels in serum and investigate their associations with post-stroke depression (PSD) in a 6-month follow-up study in Chinese patients with first-ever acute ischemic stroke (AIS). Methods: The subjects were first-ever AIS patients who were hospitalized at three stroke centers during the period from January 2015 to December 2016. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum irisin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Results: During the study period, 1205 patients were included in the analysis. There were 370 patients (30.7%) classified as depression. The depression distribution across the irisin quartiles ranged between 49.8% (first quartile) and 9.9% (fourth quartile). In the patients with depression, serum irisin levels were lower compared with those in patients without depression (P < 0.001). In a multivariate model using the first (Q1) quartile of irisin vs. Q2-4 together with the clinical variables, the marker displayed predictive information and increased risk of PSD by 75% (odds ratio [OR] for Q1, 1.75 [95% confidence interval [CI], 1.15-2.65]). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability; the area under the curve (AUC) increased from 0.77 to 0.81 (95% CI, 0.76-0.86). Conclusions: The data suggested that reduced serum levels of irisin were powerful biological markers of risk of developing PSD even after adjustment by variables. Further studies are necessary to confirm this association, which may open the way to the proposal of new therapeutic options.