Background Accumulating evidences suggest that lncRNA FOXD2‐AS1 plays an important role in tumor progression, however, its function in tongue squamous cell carcinoma (TSCC) remains unknown. This research aims to investigate the function and mechanism of FOXD2‐AS1 in the modulation of tongue squamous cell carcinoma progression. Methods Expression of FOXD2‐AS1 was detected in TSCC tissues and TCGA data. Receiver operating characteristic curves (ROCs) analysis and bioinformatic analysis of TCGA data were performed to investigate the role of FOXD2‐AS1 in TSCC prognosis. After siRNA‐mediated downregulation of FOXD2‐AS1, wound healing assay, Transwell migration and invasion assays, and MTS proliferation assay were conducted to explore the effects that FOXD2‐AS1 exerted on SCC‐9 and CAL‐27 cell lines. Western blotting was performed to detect the downstream protein changes. Results Compared to the normal tissues and samples, FOXD2‐AS1 significantly highly expressed in TSCC tissues and in TSCC samples of TCGA data, and high expression of FOXD2‐AS1 was associated with lymphatic metastasis and poor TNM stages. ROC analysis and bioinformatic analysis of TCGA data further suggested that high expression of FOXD2‐AS1 was associated with TSCC poor prognosis. Downregulation of FOXD2‐AS1 inhibited the migration and invasion of SCC‐9 and CAL‐27 cell lines. Western blotting showed that the expression of p‐p44 and p‐p65 downregulated after FOXD2‐AS1 knockdown. Conclusion High expression of FOXD2‐AS1 promotes TSCC progression through modulating NF‐kB and ERK MAPK signaling pathways and is associated with TSCC poor prognosis, it could be a novel therapeutic target and prognostic biomarker for TSCC.