This systematic review and meta-analysis aimed to compare the efficacy and safety of different drug regimens for tuberculosis preventive treatment (TPT). The analysis of 9 studies comparing rifampicin plus isoniazid (HR) and isoniazid monotherapy (H) showed no significant difference in efficacy between the two regimens (relative risk (RR): 0.89, 95% confidence interval (CI): 0.66 to 1.19, P = 0.43). However, HR was associated with significantly lower risk of adverse drug reactions (ADRs) than H (965/6478 vs 1065/6219 ADRs; RR: 0.86, 95% CI: 0.80 to 0.93, P < 0.0001). Efficacy analysis of rifampicin plus pyrazinamide (RZ) vs H showed no significant difference in infection rates between the groups (RR: 0.97, 95% CI: 0.47 to 2.03, P = 0.94). However, safety analysis showed higher risk of ADRs with RZ than H (229/572 vs 129/600 ADRs; RR: 1.87, 95% CI: 1.44 to 2.43). Safety analysis of rifampicin alone (R) vs H showed lower risk of ADRs with R than H (23/718 vs 57/718 ADRs; RR: 0.40, 95% CI: 0.25 to 0.65, P = 0.0002). In summary, while rifampicin plus isoniazid (3HP/R) was not superior to other regimens in efficacy, it was the safest regimen for TPT. Although rifampicin plus pyrazinamide (RZ) was equally efficacious, it was less safe than other regimens.