Context: The therapeutic effect, the optimal treatment time, and the dose of silymarin for preventing anti-tuberculosis and antipsychotic drug-induced liver injury (anti-TB/antipsychotic DILI) remains controversial. We conducted the first systematic review and meta-analysis study to evaluate the clinical efficacy of silymarin in the treatment of anti-TB/antipsychotic DILI in several subgroups based on follow-up time and dose. Evidence Acquisition: We searched the keywords and free words of "silymarin (silibinin)" and "Anti-tuberculosis or antipsychotic drug-induced liver injury" in PubMed, Web of Science, Cochrane, Scopus, and clinicaltrials.gov for full text English articles and China Journal Full-text Database (CNKI) and China Medical Bio-Document Database (CBM) for full text Chinese articles. The searched papers were reserved for randomized controlled trials (RCTs). The Jadad quality scale was used to conduct quality assessments. Two observers (SY and HY) independently extracted the data. MD and OR values were calculated to evaluate the clinical efficacy of silymarin in anti-TB/antipsychotic DILI. The Q test and chi-square test were used for heterogeneity analysis. Results: Nine RCTs with 2,712 participants (1,351 in the silymarin group and 1,361 in the control group) satisfying the inclusion criteria were finally examined. Compared to the placebo group, silymarin at less than 300 mg/d dose significantly reduced the occurrence of anti-TB/antipsychotic DILI and serum liver enzymes AST and ALT whether for two weeks, four weeks, or eight weeks [pooled OR: 0.53, 95% CI: 0.35-0.78, P = 0.42, I 2 = 3%; pooled MD:-4.47, 95% CI:-7.00,-1.93, P = 0.70, I 2 = 0%, AST; pooled MD:-3.50, 95% CI:-6.08,-0.91, P = 0.58, I 2 = 0%, ALT]. However, no significant difference was found in serum liver enzyme TBIL compared to the control group [pooled MD:-0.02, 95% CI:-0.07,-0.04, P = 0.69, I 2 = 0%]. Silymarin at 315 mg/d significantly reduced the occurrence of anti-TB/antipsychotic DILI and serum liver enzymes AST, ALT, and TBIL for eight weeks [subtotal OR: 0.17, 95% CI: 0.08-0.39, I 2 = 76%] but no significant difference was found between the over 400 mg/d silymarin group and the control group [subtotal OR: 0.93, 95% CI: 0.20-4.39, I 2 = 76%]. No significant difference was found in the occurrence of adverse events compared to the control group [pooled OR: 0.94, 95% CI: 0.71-1.25, I 2 = 0%]. Compared to the control group, silymarin prolonged the occurrence of anti-TB/antipsychotic DILI [pooled SMD: 1.78, 95% CI: 1.65-1.91, I 2 = 42%]. Conclusions: Silymarin prolonged the occurrence of anti-TB/antipsychotic DILI and reduced the incidence of anti-TB/antipsychotic DILI without significant adverse effects. The optimal treatment time of silymarin to prevent anti-TB/antipsychotic DILI was related to its dose.