Hypertrophic scars arise from aberrant wound healing and can lead to functional and aesthetic impairments. One of the common interventions for treating hypertrophic scars is fractional carbon dioxide (CO2) laser, which employs narrow laser beams to stimulate dermal collagen deposition. Recent studies and reports have suggested that combining laser therapy with other interventions such as botulinum toxin type A (BTX-A) and topical growth factors may enhance treatment outcomes. Here, we examine the efficacy and safety of a sequential combination of BTX-A, fractional CO2 laser, and topical growth factors, referred to as combined therapy, for treating hypertrophic scars compared with only using fractional CO2 laser and topical growth factors, referred to as monotherapy. Our retrospective study includes 128 patients with hypertrophic scars (56 underwent monotherapy and 72 underwent combined therapy), which were followed-up for up to 15 months after the initiation of treatment to collect demographic and clinical data. Our analysis showed that the combined therapy significantly outperformed monotherapy in improving Vancouver scar scale scores (P < 0.05) and in the reduction of scar thickness (P < 0.05), without increasing adverse complications. Repeated treatments further augmented the efficacy of the combined therapy. Subgroup analysis revealed that combined therapy was notably more effective in reducing Vancouver scar scale scores and scar thickness in early-stage scars compared to late-stage (P = 0.023 and P = 0.045, respectively). Our study suggests that including BTX-A treatment before fractional CO2 laser and topical growth factors offers superior efficacy in reducing hypertrophic scars. We encourage early intervention and repeated treatments for optimal treatment outcomes.