Transarterial chemoembolization (TACE) with tyrosine kinase inhibitors (TKIs) has been increasingly used to treat unresectable hepatocellular carcinoma (uHCC). However, the superiority of combination therapy to TACE monotherapy remains controversial. Therefore, here we performed a meta-analysis to evaluate the efficacy and safety of TACE plus TKIs in patients with uHCC.We searched four databases for eligible studies. The primary outcome was time to progression (TTP), while the secondary outcomes were overall survival (OS), tumor response rates, and adverse events (AEs). Pooled hazard ratios (HRs) with 95% confidence intervals (95% CIs) were collected for TTP and OS, and the data were analyzed using random-effects meta-analysis models in STATA software. OR and 95% CIs were used to estimate dichotomous variables (complete remission[CR], partial remission[PR], stable disease[SD], progressive disease[PD], objective response rate[ORR], disease control rate[DCR], and AEs) using RStudio's random-effects model. Quality assessments were performed using the Newcastle-Ottawa scale (NOS) for observational studies and the Cochrane risk of bias tool for randomized controlled trials (RCTs).The meta-analysis included 30 studies (9 RCTs, 21 observational studies) with 8246 patients. We judged the risk of bias as low in 44.4% (4/9) of the RCTs and high in 55.6% (5/9) of the RCTs. All observational studies were considered of high quality, with a NOS score of at least 6. Compared with TACE alone or TACE plus placebo, TACE combined with TKIs was superior in prolonging TTP (combined HR 0.72, 95% CI 0.65-0.80), OS (combined HR 0.57, 95% CI 0.49-0.67), and objective response rate (OR 2.13, 95% CI 1.23-3.67) in patients with uHCC. However, TACE plus TKIs caused a higher incidence of AEs, especially hand-foot skin reactions (OR 87.17%, 95%CI 42.88-177.23), diarrhea (OR 18.13%, 95%CI 9.32-35.27), and hypertension (OR 12.24%, 95%CI 5.89-25.42).Our meta-analysis found that TACE plus TKIs may be beneficial for patients with uHCC in terms of TTP, OS, and tumor response rates. However, combination therapy is also associated with a significantly increased risk of adverse reactions. Therefore, we must evaluate the clinical benefits and risks of combination therapy. Further well-designed RCTs are needed to confirm our findings.PROSPERO registration number: CRD42022298003.© 2023. The Author(s).