Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP‐10 expression in UMSCC14a (p = 0.0431) and SCC15 (p < 0.0001) cells, but decreased MMP‐9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP‐10 expression in UMSCC12 cells (p = 0.0001), and MMP‐3 (p = 0.0005) and ‐9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP‐2 (p = 0.0408) and MMP‐9 gelatinase activity (p < 0.0001), respectively. OA depletion decreased MMP‐2 (p = 0.0023) and ‐9 (p < 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p < 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion. Osteoactivin/gpnmb has been implicated in metastases, particularly bony metastases, in several malignancies. In this study we demonstrated that osteoactivin differentially upregulates matrix metalloprotease expression and activity in head and neck cancer cell lines.