Background: As a common and lethal malignancy, gastric cancer remains in urgent need of investigation of its molecular mechanisms and effective molecular targets for therapy to improve patient outcomes. MRPL3, a mitochondrial ribosomal protein, plays a critical role in protein synthesis within the mitochondrion. A number of studies have reported that MRPL3 is involved in various fatal diseases, including cancers. However, the role of MRPL3 in gastric cancer remains largely elusive. Methods: Here, we assigned 249 tissues from patients who had undergone surgical resection of early gastric cancer at The Affiliated Hospital of Medical School, Ningbo University. We examined the expression and prognostic value of MRPL3 in gastric cancer patients by using tissue microarrays, immunohistochemistry, and survival analysis. We also investigated the molecular effect of MRPL3 on gastric cancer via RNA-seq, RT-qPCR, Western blot, coimmunoprecipitation, and ubiquitination assays. Furthermore, we explored the interaction between MRPL3 and EGFR, a key factor in gastric cancer progression, and elucidated its impact on EGFR signaling and degradation. Results: We found that MRPL3 was overexpressed and correlated with poor survival in gastric cancer and that MRPL3 knockdown significantly impeded the proliferation, invasion, and tumor growth of gastric cancer. Furthermore, MRPL3 activated the EGFR/STAT1 signaling pathway by inhibiting the ubiquitination and degradation of EGFR, and knockdown of MRPL3 had an inhibitory effect on the progression of gastric cancer. Finally, the upregulation of EGFR expression reversed the anti-gastric cancer effect of MRPL3 knockdown both in vitro and in vivo. Conclusion: Our study reveals a novel mechanism by which MRPL3 plays an indispensable role in promoting gastric cancer progression by activating the EGFR/STAT1 signaling pathway through inhibiting the ubiquitination and degradation of EGFR. Therefore, MRPL3 could be a potential therapeutic target for gastric cancer.