Background Endoscopic injection of cyanoacrylate into gastric varices may be performed by EUS-guided fine needle injection (EUS-FNI) or direct endoscopic injection (DEI). The aim of this study is to compare the rate of recurrent GV bleeding and adverse events between DEI and EUS-FNI for treatment of GV. Methods In a single-center study, a retrospective cohort of patients with actively/recently bleeding or high-risk GV treated with DEI were compared with a prospective cohort of similar patients treated with EUS-FNI. Repeat endoscopy after index treatment was performed 3 months later or earlier if rebleeding occurred. The main outcomes assessed were rates of GV or overall rebleeding and adverse events. Results Forty patients (mean age 57.2 ± 9.1 years, 73% male) and 64 patients (mean age 58.0 ± 12.5 years, 52% male) underwent DEI and EUS-FNI, respectively. Compared to the DEI group, the frequency of isolated gastric varices type 1 (IGV1) were higher ( p  < 0.001) but MELD scores were lower ( p  = 0.004) in the EUS-FNI group. At index endoscopy, EUS-FNI utilized a lower mean volume of cyanoacrylate (2.0 ± 0.8 mL vs. 3.3 ± 1.3 mL; p  < 0.001) and injected a greater number of varices (1.6 ± 0.7 vs. 1.1 ± 0.4; p  < 0.001) compared to DEI. Overall, GV rebleeding 5/57 (8.8%) vs. 9/38 (23.7%); p  = 0.045 and non-GV-related gastrointestinal bleeding 7/64 (10.9%) vs. 11/40 (27.5%); p  = 0.030 were less frequent in the EUS-FNI group compared to the DEI group, respectively. Adverse event rates were similar (20.3% vs. 17.5%, p  = 0.723). Conclusions EUS-guided CYA injection of active or recently bleeding GV in patients with portal hypertension appears to decrease the rate of GV rebleeding despite injection of more varices and less CYA volume during the initial endoscopic procedure. Adverse events are similar between the two groups. EUS-FNI appears to be the preferred strategy for treatment of these patients.