Alopecia areata (AA) is a common cause of hair loss with no available universally successful treatment. Thus, new innovative treatments are urgently needed. This research aimed to evaluate the effectiveness of fractional carbon dioxide laser (FCL) alone or combined with triamcinolone acetonide (TA) solution, platelet-rich plasma (PRP), or vitamin D3 solution in treating AA. Sixty-four AA patients with 185 lesions were recruited and divided into four treatment groups. All patients received FCL either alone (group A, n = 19) or followed by topical TA (group B, n = 16) or PRP (group C, n = 15), or vitamin D3 solution (group D, n = 14). The response was assessed using Alopecia Areata Severity Index (AASI), MacDonald Hull and Norris grading, and trichoscopy. Histopathological features and immunohistochemical decorin expression were studied. All groups showed significant improvement in AASI compared to the baseline, with insignificant differences between them. Post-treatment, trichoscopic features of disease activity significantly decreased in all groups. Compared to control biopsies, both anagen follicles and decorin expression were significantly decreased in all pretreatment specimens. After treatment, all groups showed significantly increased anagen follicles and decorin expression compared to the baseline. Accordingly, FCL is an effective treatment for AA alone or combined with TA, PRP, or vitamin D3 solution. In AA, Decorin expression was downregulated, while enhanced expression following successful treatment occurred. This suggests the role of decorin in AA pathogenesis. However, further research is still recommended to clarify the exact role of decorin in AA pathogenesis and to investigate the therapeutic benefits of decorin-based therapy.