Objective: Our study aims to investigate the expression of human epidermal growth factor receptor 2 (HER-2), Janus-activated kinase/signal transducer, and activator of transcription 3-suppressor of cytokine signaling 3 (JAK/STAT3-SOCS3) pathway in gastric cancer (GC) and its relationship with clinicopathological features and prognosis of GC. Materials and Methods: A total of 105 GC patients who underwent surgical resection were enrolled for our study, and corresponding 60 normal tissues adjacent to carcinoma (>10 cm from the carcinoma tissues) as control groups. Spearman correlation analysis was applied for correlation analysis among HER-2, STAT3, and SOCS3. Kaplan-Meier method and Cox proportional hazard model were applied for investigating the associations among HER-2, STAT3 and SOCS3 expressions and prognosis of GC patients. Results: The expressions of HER-2 and STAT3 in GC tissues were increased, but SOCS3 expression showed an evident decrease with the change of depth of invasion, lymph node metastasis (LNM), and tumor node metastasis staging (all P < 0.05). The result of Spearman correlation analysis showed a positive correlation between HER-2 and STAT3 (r = 0.216, P < 0.05), while a negative correlation was observed between STAT3 and SOCS3 (r = -0.237, P < 0.05). Kaplan-Meier analysis results showed that the survival time of HER-2 and STAT3 negative group were both higher than their positive group (both P < 0.001), nevertheless, the survival time of SOCS3 negative group was lower than positive group (P < 0.001). Cox regression multivariate analysis indicated HER-2, STAT3, SOCS3, LNM, and depth of invasion were independent prognostic factors influenced the prognosis of GC (all P < 0.001). Conclusion: Our study revealed that HER-2 may participates in the development, invasion and metastasis of GC by affecting the JAK/STAT3 pathway. HER-2, STAT3, and SOCS3 serve as reference indexes for the prognosis of GC patients.