The aim of the present article is to test at a meta-analytical level the efficacy and safety of second-generation long-acting antipsychotic injections (SGLAI) in schizophrenia. Thirteen randomized-controlled trials comparing SGLAI with either placebo or oral antipsychotics were included in a quantitative meta-analysis (6313 patients). Efficacy and safety measures as well as demographic and clinical variables were extracted from each publication or obtained directly from authors. Publication bias was assessed with funnel plots and Egger’s intercept. Heterogeneity was addressed with the Q statistic and the I2 index. SGLAI were more effective than placebo injections [Hedges’s g=0.336, 95% confidence interval (CI) 0.246–0.426, Z=7.325, P<0.001] in reducing the Positive and Negative Syndrome Scale (PANSS) scores, but no differences were observed compared with oral antipsychotics (Hedges’s g=0.072, 95% CI −0.072 to 0.217, Z=0.983, P=0.326). There were more responders under SGLAI than placebo (47 vs. 24%, NNT 4, 95% CI 3–6), but no differences in comparison with oral antipsychotics [relative risk (RR)=0.962, P=0.094]. SGLAI and controls groups shared a common safety profile with respect to the number of deaths, overall number of treatment-adverse events, insomnia, QT prolongation, or pain in the injection site. There was a greater risk of developing extrapyramidal side effects with SGLAI than with placebo (RR=2.037, P<0.001) or with oral antipsychotics (RR=1.451, P=0.048). There was no evidence of publication bias (Egger’s P=0.476), and sensitivity analysis confirmed the robustness of results. The present meta-analysis shows superior efficacy for the SGLAI over placebo on psychotic symptoms, although with a relatively small effect size; no evidence of superiority in efficacy over oral antipsychotics; and modest evidence of greater symptoms of extrapyramidal side effects. These data suggest that SGLAI lack an advantage in reducing psychotic symptoms over oral medications. Their potential effects on relapse prevention should be better addressed by future randomized-controlled trials.