Objective To analyze the correlation of expression levels of serum micro-ribonucleic acid-92a-1-5p (miR-92a-1-5p) and miR-92a-2-5p with post-stroke depression in elderly patients. Methods A total of 129 elderly stroke patients admitted in our hospital from February 2018 to October 2020 were selected as the study group, and another 110 healthy subjects who took physical examination at the same period were recruited as control group. The expression of serum miR-92a-1-5p and miR-92a-2-5p of all the subjects were detected with quantitative real-time polymerase chain reaction. Hamilton depression scale-17 was used to evaluate the depression in the study group within 1 month after admission. SPSS statistics 23.0 was used for data analysis. According to the data type, one-way analysis of variance or Chi-square test was employed for comparison between groups. Logistic regression analysis was adopted to analyze the influencing factors of depression in elderly stroke patients. Results The expression levels of miR-92a-1-5p and miR-92a-2-5p were significantly higher in the study group than the control group (P<0.05). In the study group, 37.98% (49/129) patients were complicated with depression in 1 month after admission. And the depressive patients had obviously higher levels of the two molecules than those without depression (P<0.05). Female, National Institutes of Health stroke scale score, basal ganglia lesions, left frontal lobe lesions, education level above high-middle school, decreased family support, and elevated serum levels of miR-92a-1-5p and miR-92a-2-5p were risk factors of post-stroke depression in elderly patients (P<0.05). Conclusion Higher expression levels of serum miR-92a-1-5p and miR-92a-2-5p indicate increased risk for depression in elderly stroke patients.