Oral cancer is among the top 10 most prevalent forms of cancer worldwide, characterized by a highly diverse group of tumors and the absence of specific biomarkers and poor prognosis. It is evident that oral squamous cell carcinoma (OSCC) is the most prevalent form of oral cancer in developing nations, particularly in Southeast Asia and southern Africa. Despite recent advances in the treatment modalities, including surgery, chemotherapy, and radiotherapy, the mortality rate of OSCC (mainly due to lymphatic involvement and metastasis) continues to rise, presenting both patients and healthcare systems with a challenge. It has been shown that tumors are heterogeneous due to the presence of different kinds of cancer cells. In addition to these populations of cells, cancer stem cells (CSCs) contribute substantially to the initiation and progression of cancer. The CSCs are also capable of self-renewal and differentiation, similar to their stem cell counterparts. The mesenchymal SCs (MSCs) are a specific population of CSCs which differentiate into mesodermal cells. The characteristics of MSCs include self-renewal, rapid proliferation, multipotent differentiation, and low immunogenicity. Furthermore, because MSCs are particularly prone to delivering therapeutic agents and transferring genetic material to injured tissues and tumors, they are excellent candidates for use as cell carriers. There has been a significant amount of research regarding the potential pro-or antitumorigenic effect of MSCs on the progression and initiation of tumors. The interaction between tumor cells and MSCs within the tumor microenvironment plays an important role in tumor progression. It is important to note that MSCs are recruited to the site of wound healing in order to repair damaged tissues, a process that is also related to tumorigenesis. Alternatively, resident or migrating MSCs may favor tumor angiogenesis and make the tumor more aggressive. The interaction between MSCs and cancer cells is fundamental to the development, progression, and metastasis of cancer. Therefore, an interesting topic is the relationship between cancer cells and MSCs, since contrasting reports about their respective influences have been reported. In this review, we discuss recent findings related to conflicting results on the influence of MSCs in cancer development and its management.