Objective To investigate the association between Helicobacter pylori （Hp） infection and the expression levels of p27， CyclinD1， matrix metalloproteinase 9 （MMP-9）， and related microRNAs， as well as their correlations with clinicopathological characteristics in gastric cancer （GC） tissues. Methods A total of 116 GC patients who underwent surgical resection were enrolled and classified into Hp-positive and Hp-negative groups based on Hp infection status， consisting of 76 and 40 cases， respectively. Among the Hp-positive group， patients were further categorized into good prognosis and poor prognosis subgroups according to their clinical outcomes， with 56 and 20 cases， respectively. The expression levels of p27， CyclinD1， MMP-9 proteins， as well as miR-490-3p and miR-146a in both cancerous and paracancerous tissues across the groups were compared. Additionally， the associations between the expression of these biomarkers in cancer tissues and the clinicopathological features and prognosis of Hp-positive GC patients were analyzed. Furthermore， potential risk factors contributing to poor prognosis in Hp-positive GC patients were identified， and a predictive model was constructed to evaluate its prognostic value. Results The expression levels of p27 protein and miR-490-3p in GC tissues were significantly lower compared to those in adjacent non-cancerous tissues， whereas the expression levels of CyclinD1， MMP-9 protein， and miR-146a were significantly higher （P < 0.05）. In cancer tissues from the Helicobacter pylori （Hp）-positive group， the expression of p27 protein and miR-490-3p was lower than that in the Hp-negative group， while the expression of CyclinD1， MMP-9 protein， and miR-146a was higher （P < 0.05）. Moreover， in Hp-positive GC patients， the expression levels of p27 protein and miR-490-3p in cancer tissues were lower in those with advanced stages （Ⅲ ~ Ⅳ） and lymph node metastasis compared to those with early stages （Ⅰ ~ Ⅱ） and no lymph node metastasis （P < 0.05）. Conversely， the expression levels of CyclinD1， MMP-9 protein， and miR-146a were higher in patients with advanced stages and lymph node metastasis （P < 0.05）. Compared with the good prognosis group， the poor prognosis group exhibited a higher proportion of advanced stages， lymph node metastasis， and elevated expression levels of CyclinD1， MMP-9 protein， and miR-146a， while the expression levels of p27 protein and miR-490-3p were reduced （P < 0.05）. Multivariate analysis indicated that advanced stage （Ⅲ ~ Ⅳ）， low expression of p27 protein， high expression of MMP-9 protein， and low expression of miR-490-3p were independent risk factors for poor prognosis in Hp-positive GC patients （P < 0.05）. The predictive model constructed for assessing the likelihood of poor prognosis in Hp-positive GC demonstrated an area under the curve （AUC） of 0.774， with a sensitivity of 80.00% and a specificity of 76.79%. Conclusions p27， CyclinD1， MMP-9 protein， miR-146a， and miR-490-3p were found to be abnormally expressed in patients with Hp-positive GC. Their expression levels were significantly associated with TNM stage and the presence of lymph node metastasis. Specifically， Stage Ⅲ ~ Ⅳ disease， low expression of p27 protein and miR-490-3p， and high expression of MMP-9 protein were identified as independent risk factors for poor prognosis in patients with Hp-positive GC. A predictive model based on these risk factors demonstrated favorable performance in forecasting poor clinical outcomes in this patient population.