Gastric cancer (GC) is one of the most commonly diagnosed malignancies worldwide, especially in East Asia. Discovery of new biomarker and the elucidation of the molecular mechanisms involved in GC development and progression continue to be important issues for both researchers and clinicians. In the present study, we report that siRNA knockdown of heat shock protein family B (small) member 8 (HSPB8) inhibited the proliferation of GC cells and promoted their apoptosis. Analysis of TCGA dataset indicated that the HSPB8 expression level was strongly positively correlated with the KEGG MAPK signaling pathway (P<0.001, FDR=0.006) and BIOCARTA CREB pathway (P=0.006, FDR=0.043). The association between HSPB8 and the ERK-CREB pathway was confirmed by western blot analysis and we found that pERK and pCREB were significantly decreased following HSPB8 knockdown. Downstream genes of the ERK-CREB pathway were all significantly decreased following HSPB8 knockdown. By evaluating the survival of TCGA GC patients, we found that patients with a high HSPB8 level exhibited significantly worse prognosis than those with low HSPB8 in both overall survival (OS) (log-rank chi(2)=10.60, P=0.001) and disease-free survival (DFS) (log-rank chi(2)=11.31, P<0.001). The methylation level of HSPB8 DNA was significantly negatively associated with its expression (R=-0.1368, P=0.041), and positively associated with OS (log-rank chi(2)=10.60, P=0.001). In conclusion, we provide evidence that HSPB8 promotes cancer cell growth by activating the ERK-CREB pathway and may serve as a potential prognostic factor in GC patients.