The guide recommends SSRI and SNRI drugs as first-line treatments for generalized anxiety disorder (GAD). Therefore, we aimed to update the evidence using network meta-analysis by comparing the efficacy and acceptability of first-line drugs. The relevant electronic databases were searched for placebo-controlled and head-to-head trials of 11 drugs used for the acute treatment of adults with GAD from 1980 up to January 1, 2019. Data on demographics, clinical, and treatment information were extracted from each eligible study. The primary outcomes were efficacy (quantified as the change in the total score on the Hamilton Anxiety Scale from baseline) and acceptability (quantified as treatment discontinuations due to any cause). Overall, the data on 41 RCTs were sufficient or appropriate for inclusion. In terms of efficacy, all of the drugs except fluoxetine and vortioxetine were more effective than placebo, with the weighted mean difference of the Hamilton Anxiety Scale score ranging between −3.2 (95% credible interval [CrI] = −4.2 to −2.2) for escitalopram and −1·8 (95% CrI = −3.1 to −0.55) for vilazodone. For acceptability, only vilazodone (OR = 1.7, 95% CrI = 1.1 to 2.7) were worse than placebo, others did not show significant differences from placebo. In head-to-head comparisons, vortioxetine showed better acceptability and tolerability but worse efficacy and response rate. In conclusion, most drugs are more effective than placebo, and there are few significant differences between the active drugs and placebo on acceptability. Overall, duloxetine and escitalopram showed better efficacy while vortioxetine showed better acceptability.