Gingival squamous cell carcinoma (GSCC) displays strong potential for local infiltration. Detailed evaluation of bone invasion to the mandible is an important problem clinically. The purpose of this study was to investigate the expression of osteoclast‐related cytokines, which play an important role in mandibular invasion. A total of 23 cases of lower GSCC were classified histopathologically as non‐invasive group (n = 10) or invasive group (n = 13). Cytokines of interleukin (IL)‐1α, IL‐1β, IL‐6, IL‐11, tumor necrosis factor (TNF)‐α, parathyroid hormone‐related protein (PTHrP), receptor activator of nuclear factor κB (RANK), RANK ligand (RANKL), and osteoprotegerin (OPG) were selected. In this prospective study, the expressions of these cytokines were studied by quantitative real‐time reverse transcription‐polymerase chain reaction. IL‐1α, IL‐1β, IL‐6, TNF‐α, PTHrP, and RANKL were expressed higher in the invasive group. In particular, IL‐6 was considered as a non‐specific cytokine which responds to inflammatory change by tumor or non‐tumor stimulation. These results suggest that IL‐1α, IL‐1β, IL‐6, TNF‐α, PTHrP, and RANKL play important roles in the mechanisms underlying mandibular invasion. Furthermore, expression analysis of OPG/RANK/RANKL system may contribute to treatment and prevention of GSCC in future.