Objective. To systematically evaluate the effect and safety of compound Kushen injection (CKI) as an add-on treatment on the treatment for breast cancer. Methods. We searched eight major electronic databases from their inception to November 1, 2021, for randomized clinical trials (RCTs) comparing CKI plus chemotherapy with chemotherapy alone. Primary outcomes included objective response rate (ORR) and disease control rate (DCR), health-related quality of life (HRQoL), progression-free survival (PFS), and overall survival (OS). Secondary outcomes included adverse drug reactions (ADRs) and tumor marker level. We used Cochrane’s RevMan 5.3 for data analysis. The GRADEpro was used to appraise the certainty of evidence. Trial sequential analysis (TSA) was applied to estimate the required sample size in a meta-analysis and test the robustness of the current results. Results. Thirty RCTs with 2556 participants were totally included. CKI plus chemotherapy showed significant effects in increasing ORR (RR 1.30, 95%CI [1.18, 1.43], I2 = 27%, n = 1694), increasing DCR (RR 1.21, 95%CI [1.15, 1.28], I2 = 16%, n = 1627), increasing HRQol as measured by Karnofsky Performance Scale (KPS) score improvement rate (RR 1.42, 95% CI [1.26, 1.61], I2 = 37%, n = 1172), increasing the PFS (MD 2.24 months, 95%CI [1.26, 3.22], n = 94) and the OS (MD 2.24 months, 95%CI [1.45, 3.43], n = 94), compared to chemotherapy alone. The results showed that CKI plus chemotherapy had a lower risk of ADRs than that of chemotherapy alone group. The certainty of evidence of the included trials was generally low to very low. TSA for ORR and KPS score improvement rate demonstrated that the current results reached a sufficient power regarding both numbers of trials and participants. Conclusions. Low certainty of evidence suggested that the combination of CKI and conventional chemotherapy appeared to improve ORR, DCR, and KPS score in breast cancer patients. Conclusions about PFS and OS could not be drawn due to lack of evidence. Additionally, CKI appeared to relieve the risk of ADRs in patients with breast cancer receiving chemotherapies. However, due to weak evidence, the findings should be further confirmed in large and rigorous trials.