To assess the efficiency and the mechanism of fractional erbium:yttrium aluminum garnet (Er:YAG) laser for the treatment of morphea in mouse model. Morphea is a rare autoimmune disease characterized by excessive collagen deposition in skin. Fractional Er:YAG laser treatment is a promising treatment to improve morphea, despite limited studies about the therapeutic effect and underlying mechanism. The mouse model of morphea was established by subcutaneously injecting with bleomycin (BLM). A total of 24 mice received fractional Er:YAG laser treatment once a week for 4 weeks. Objective measurement employed was ultrasonic imaging to measure dermal thickness. Subjective measures included scoring according to the adjusted Localized morphea Cutaneous Assessment Tool (LoSCAT); hematoxylin and eosin (H&E) staining to evaluate the histological grade of fibrosis; and quantitative morphometric studies to determine the expression of transforming growth factor-β1 (TGF-β1) and matrix metalloproteinase-1 (MMP1) by immunohistochemistry. In this self-controlled study, fractional Er:YAG laser treatment significantly ameliorate the severity of morphea, including lower clinical score (p < 0.01), decreased dermal thickness (p < 0.001), declined histological grade of fibrosis (p < 0.001), increased MMP1 (p < 0.001), and reduced TGF-β1 (p < 0.01) expression. We found that fractional Er:YAG laser treatment of morphea has good clinical, ultrasonic, and histopathologic efficacy, which may be a promising treatment in the future.