Aberrant scar formation, which includes keloid and hypertrophic scars, is associated with a pathological disorganized wound healing process with chronic inflammation. The TGF-β/Smad signaling pathway is the most canonical pathway through which the formation of collagen in the fibroblasts and myofibroblasts is regulated. Sustained activation of the TGF-β/Smad signaling pathway results in the long-term overactivation of fibroblasts and myofibroblasts, which is necessary for the excessive collagen formation in aberrant scars. There are two categories of therapeutic strategies that aim to target the TGF-β/Smad signaling pathway in fibroblasts and myofibroblasts to interfere with their cellular functions and reduce cell proliferation. The first therapeutic strategy includes medications, and the second strategy is composed of genetic and cellular therapeutics. Therefore, the focus of this review is to critically evaluate these two main therapeutic strategies that target the TGF-β/Smad pathway to attenuate abnormal skin scar formation.