Objective To investigate the effect and mechanism of action of CKLF-like MARVEL transmembrane domain-containing6（CMTM6） targeting human epidermal growth factor receptor 2（HER2） on the proliferation，invasion，migration，and apoptosis of gastric cancer cells. Methods RT-qPCR and Western blot were used to measure the expression level of CMTM6 in gastric cancer tissue，normal paracancerous tissue，and gastric cancer cells. After AGS and BGC-823 cells were transfected with sh-NC and sh-CMTM6，CCK8 assay，Transwell assay，and flow cytometry were used to detect cell proliferation，invasion，migration，and apoptosis. Co-immunoprecipitation（Co-IP） was used to detect the binding between CMTM6 and HER2，and cycloheximide（CHX） was used to investigate the effect of low-expression CMTM6 on HER2 protein stability. Results The mRNA and protein expression levels of CMTM6 in gastric cancer tissue were significantly higher than those in normal paracancerous tissue（P<0.05）. The low expression of CMTM6 significantly inhibited the proliferation，invasion，and migration of AGS and BGC-823 cells and promoted cell apoptosis（P<0.05），while overexpression of CMTM6 significantly promoted the proliferation，invasion，and migration of AGS and BGC-823 cells and inhibited cell apoptosis. Co-IP showed the existence of binding between CMTM6 and HER2，and the low expression of CMTM6 significantly inhibited the expression of HER2 protein（P<0.05） and reduced HER2 protein stability（P<0.05）. Co-transfection of LV-CMTM6 and sh-HER2 in AGS and BGC-823 cells could reverse the effect of CMTM6 overexpression on the proliferation，invasion，migration，and apoptosis of AGS and BGC-823 cells. Conclusion CMTM6 is significantly highly expressed in gastric cancer tissue and cells. CMTM6 can promote HER2 protein stability through targeted binding to HER2，thereby promoting the proliferation，invasion，and migration of gastric cancer cells and inhibiting the apoptosis of gastric cancer cells.