Introduction <p>Depression after a stroke is the most frequent and burdensome neuropsychiatric post-stroke complication. This study aimed to determine the relationship between post-stroke depression (PSD) and the levels of homocysteine (HCY) in patients with spontaneous intracerebral hemorrhage (SICH).</p> Method <p>We collected data from patients with hemorrhagic stroke (HS) admitted to the hospital and recorded their demographic and clinical characteristics. We also searched for information regarding HAM-D₁₇ (Hamilton Depression) scores and HCY levels at 3&#xa0;m, the use of antidepressant medications and folic acid during the follow-up period in the group of patients diagnosed with PSD and hyperhomocysteinemia (HHcy) in the acute phase.</p> Result <p>A total of 1,852 patients were included. 642 (34.7%) patients with PSD and 598 (32.3%) patients with HHcy, 364 (19.7%) patients with both conditions. A link between depression and low HCY level has similarly been found in patients with HS (OR, 1.549; 95% CI, 1.358–1.768). Additionally, left-sided stroke, anterior circulatory stroke, intraventricular hemorrhage, symptoms of paralysis or dysarthria, and higher NIHSS scores occurred more often in the PSD group. Compared to the antidepressant medications (ADM) group, HAM-D₁₇ scores decreased significantly in the ADM plus folic acid group at the end of 3&#xa0;m (<i>P</i> = 0.036).</p> Conclusion <p>On the basis of our data, PSD was significantly more frequent in patients with HHcy in patients with SICH at the acute phase. The location of hemorrhage and the severity of the disease are significantly correlated with the incidence of PSD. Oral doses of folic acid and ADM showed significant improvements in the HAM-D₁₇ scores for the patients with comorbid PSD and HHcy.</p>