Background. Gastric low-grade intraepithelial neoplasia (LGIN) is a precancerous lesion of gastric cancer. Endoscopic therapies represented by radiofrequency ablation (RFA) and argon plasma coagulation (APC) have been applied to treat gastric LGIN in recent years. However, no comparative study examining the effectiveness and safety profiles of RFA and APC has been reported. Methods. A single-center, large-scale, retrospective study, including 73 and 50 patients treated with RFA and APC, respectively, was conducted in the First Medical Center of Chinese PLA General Hospital from October 2015 to October 2020, with a two-year follow-up. Effectiveness, complications, operative factors, and other data were assessed. Results. At 2 years of follow-up, cure, relapse, recurrence, and progression rates were 90.4%, 9.6%, 9.6%, and 2.7% in the RFA group, respectively, versus 90%, 10%, 12%, and 4% in the APC group, respectively, with no statistically significant differences between the two groups (all
p
>
0.05
). However, the mean lesion size was significantly larger in the RFA group (2.6 ± 1.0 cm) than in the APC group (1.5 ± 0.6 cm) (
p
<
0.001
); there was also a significant difference in the composition ratio of large lesions between the two groups (
p
<
0.001
). No serious postoperative complications showed in either group, and the abdominal pain was the most common symptom in the short term after surgery. Conclusions. RFA and APC are both safe and effective destructive therapies for gastric LGIN. RFA is more suitable for flat and large lesions, while APC is more suitable for small lesions, especially those with slight local uplift or depression. An intraoperative submucosal injection is expected to be an effective method for relieving postoperative abdominal pain.