Fibrotic lesions play a key role in conditions involving connective tissue such as Scleroderma and Oral Submucous Fibrosis (OSF), leading to the development of tissue similar to scars that limit function and raise the risk of complications. This review contrasts Scleroderma, an autoimmune disorder resulting in systemic fibrosis in various organs, with OSF, a condition mainly triggered by prolonged irritation and inflammation of the oral mucosa, commonly related to areca nut consumption. Both conditions are defined by gradual fibrosis, resulting in notable limitations in functionality and a substantial decline in quality of life for patients. Scleroderma's development includes a complicated combination of autoimmunity, genetic elements, and environmental factors, resulting in broad systemic impacts. On the other hand, the development of OSF is primarily centered around the oral cavity due to environmental factors, genetic susceptibility, and nutritional deficiencies. In terms of epidemiology, Scleroderma is more prevalent among women in their middle age around the world, whereas OSF mainly impacts younger men in South Asia. In clinical terms, Scleroderma is characterized by thickened skin and fibrosis of organs, while OSF is identified by trismus, mucosal blanching, and a risk of turning malignant. The review emphasizes the significance of recognizing the unique and common features of these conditions to enhance diagnostic precision and direct individualized treatment plans. The aim of this analysis is to improve treatment results and patient care for individuals with Scleroderma and OSF.