This systematic review and meta-analysis aimed to analyze the efficacy and safety of Sihogayonggolmoryeo-tang (SGYMT), a classical herbal medicine consisting of 11 herbs, for treatment of post-stroke depression (PSD). Thirteen databases were comprehensively searched from their inception dates until July 2019. Only randomized controlled trials (RCTs) using SGYMT as a monotherapy or adjunctive therapy for PSD patients were included. Where appropriate data were available, meta-analysis was performed and presented as risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CIs). We assessed the quality of RCTs using the Cochrane risk of bias tool and the Jadad scale. The quality of evidence for each main outcome was evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Twenty-one RCTs with 1,644 participants were included. In the comparison between the SGYMT and antidepressants groups, the SGYMT group scored significantly lower on both the Hamilton Depression Scale (HAMD) (8 studies; MD -2.08, 95% CI -2.62 to -1.53, I2 = 34%) and the National Institutes of Health Stroke Scale (NIHSS) (2 studies; MD -0.84, 95% CI -1.40 to -0.29, I2 = 19%), and significantly higher on the Barthel index (3 studies; MD 4.30, 95% CI 2.04 to 6.57, I2 = 66%). Moreover, the SGYMT group was associated with significantly fewer adverse events (6 studies; RR 0.13, 95% CI 0.05 to 0.37, I2 = 0%) than the antidepressants group. In the subgroup analysis, SGYMT treatment consistently reduced HAMD scores within the first 8 weeks of treatment, but thereafter this difference between groups disappeared. Comparisons between SGYMT combined with antidepressants, and antidepressants alone, showed significantly lower scores in the combination group for both HAMD (7 studies; MD = -6.72, 95% CI = -11.42 to -2.01, I2 = 98%) and NIHSS scores (4 studies; MD -3.03, 95% CI -3.60 to -2.45, I2 = 87%). In the subgroup analysis, the reductions of HAMD scores in the SGYMT combined with antidepressants group were consistent within 4 weeks of treatment, but disappeared thereafter. The quality of RCTs was generally low and the quality of evidence evaluated by the GRADE approach was rated mostly "Very low" to "Moderate." The main causes of low quality ratings were the high risk of bias and imprecision of results. Current evidence suggests that SGYMT, used either as a monotherapy or an adjuvant therapy to antidepressants, might have potential benefits for the treatment of PSD, including short-term reduction of depressive symptoms, improvement of neurological symptoms, and few adverse events. However, since the methodological quality of the included studies was generally low and there were no large placebo trials to ensure reliability, it remains difficult to draw definitive conclusions on this topic. Further well-designed RCTs addressing these shortcomings are needed to confirm our results.