Skin fibrosis caused by excessive collagen synthesis and deposition in the dermis affects the quality of daily life of hundreds of thousands of people around the world. The skin quality, including its smoothness in young age and wrinkly during the aging process, depends largely on the levels of extracellular matrix proteins such as collagen in skin. As physiological levels of collagen are desirable for skin homeostasis, beauty, and its flexibility, too much collagen deposition in the skin is associated with tight hard skin, loss of adipose layer, and flexibility, the pathological manifestations of skin fibrosis in fibrotic diseases such as scleroderma. To understand the molecular basis of skin fibrosis and in search of its therapy, different cellular, molecular, epigenetic, and preclinical studies have been undertaken to control abnormal excessive synthesis and accumulation of matrix protein collagen. Over the last two decades, numerous phase 1 through 3 clinical trials have been conducted to test the safety and efficacy of a wide variety of compounds in amelioration of skin fibrosis and other pathologies in scleroderma, yet, no effective therapy for skin fibrosis is available. This article solely focuses on the role of a nuclear receptor and transcription factor, peroxisome proliferator-activated receptor-gamma (PPAR-γ), as an anti-skin fibrotic driving force and the potential therapeutic efficacies of PPAR-γ-specific ligands/agonists including antidiabetic drugs and other natural or semi-synthetic compounds derived from cannabis in amelioration of skin fibrosis in scleroderma. The underlying molecular basis of agonist-activated PPAR-γ-mediated suppression of profibrogenic signaling and skin fibrogenesis is also highlighted.