Objective To investigate the effect and mechanism of long non-coding RNA (LncRNA) FGD5-AS1 on the proliferation, apoptosis, migration, and invasion of oral squamous cell carcinoma (OSCC) cells. Methods FGD5- AS1 expression in OSCC was analyzed using an online database. Tumor and normal tissues of 30 patients with OSCC collected at the Stomatology Department of Tengzhou Central People’s Hospital, and human oral mucosal cell line HOK and OSCC cell lines SCC-9, HSC-4, SCC-25, and CAL-27 cultured in vitro were investigated. qRT-PCR was performed to measure FGD5-AS1 and miR-129-5p expression. CAL-27 cells with the highest FGD5-AS1 expression were divided into Control, si-NC, si-FGD5-AS1, si-FGD5-AS1+NC inhibitor, and si-FGD5-AS1+miR-129-5p inhibitor groups. CCK-8 and colony formation assays were used to assess cell proliferation. Apoptosis was detected by flow cytometry. Cell migration was assessed by wound healing assays. Transwell chambers were used to assess cell invasion. Dual luciferase reporter assays were sued to verify the targeting relationship between FGD5-AS1 and miR-129-5p. Expression of high mobility group protein B1 (HMGB1) was detected by Western blot. An In vivo xenograft tumor model was established and divided into sh- NC, sh-FGD5-AS1, miR-129-5p inhibitor, and sh-FGD5-AS1+miR-129-5p inhibitor groups. The tumor volume and tumor were assessed. qRT-PCR was used to measure FGD5-AS1 and miR-129-5p expression in transplanted tumor tissues. HMGB1 and Ki67 expression was detected by immunohistochemistry. Results Database analysis showed that the expression level of FGD5-AS1 in OSCC tumor tissues was 4 times higher than that in normal tissues. FGD5-AS1 expression was associated with a poor grade in OSCC patients. Compared with normal tissues and human oral mucosal cells, FGD5- AS1 expression in tumor tissues and OSCC cell lines was significantly increased, and miR-129-5p expression was significantly decreased ( P< 0. 05). CAL-27 cells with the highest expression level of FGD5-AS1 were selected for transfection experiments. Silencing FGD5-AS1 increased the apoptosis rate, decreased cell viability, the scratch healing rate, and number of invaded cells, enhanced miR-129-5p expression, and downregulated HMGB1 expression (P<0. 05). MiR-129-5p was the target gene of FGD5-AS1. Inhibition of miR-129-5p expression reversed the effects of silencing FGD5- AS1 on OSCC cell proliferation, apoptosis, migration, and invasion. In vivo experiments showed that FGD5-AS1 silencing significantly inhibited tumor growth and expression of HMGB1 and Ki67 (P<0. 05), and inhibition of miR-129-5p result ed in the opposite trend. Inhibition of miR-129-5p reversed the effects of FGD5-AS1 inhibiton on tumor growth and expression of HMGB1 and Ki67 (P<0. 05). Conclusions FGD5-AS1 is upregulated in OSCC cells. Interfering with FGD5-AS1 expression inhibit the proliferations, migration, and invasion of OSCC cells and promotes apoptosis by targeting the miR- 129-5p/ HMGB1 axis.