The flotillin (Flot) protein family has been demonstrated to be involved in the development and progression of various cancers. However, the role of Flot2 in gastric carcinomas remains unknown. The present study aimed to investigate the clinical significance and the role of Flot2 in gastric carcinomas. Data of tissue microarray including 90 cases of gastric carcinoma samples and their matched adjacent tissues showed that, among 90 cases of adjacent tissues, 65 cases showed no Flot2 expression, and 25 cases showed low expression of Flot2, and its positive expression rate was only 38.5% (25/90); however, among 90 cases of gastric carcinomas, 6 cases showed no Flot2 expression, 26 cases showed low Flot2 expression, 28 cases showed moderate expression of Flot2, and 30 cases showed high expression of Flot2, and its positive expression rate was 93.3% (84/90). Moreover, the Flot2 expression was significantly associated with the histological grade, depth of invasion, lymph node metastasis, and TNM stage. Furthermore, data of survival analysis suggested that Flot2 protein expression was an independent prognostic factor of poor survival. After that, Flot2-specific siRNA was used to decrease the Flot2 expression in gastric cancer AGS and SGC7901 cells. Forced downregulation of Flot2 remarkably inhibited cellular proliferation, migration, and invasion in gastric carcinoma cells. In conclusion, the present study suggests that the Flot2 protein expression is significantly correlated with cancer progression and poor prognosis in gastric carcinomas, probably due to its role in the regulation of cell proliferation, migration, and invasion in gastric carcinoma cells.