Introduction: Vitiligo poses a significant challenge, particularly in treatment-resistant areas such as acral regions. This study aimed to evaluate the effectiveness and safety of combining fractional CO2 laser and microneedling with conventional therapies for non-segmental vitiligo in resistant areas. Methods: A randomized clinical trial with a paired design was conducted on 84 individuals with non-segmental vitiligo and treatment-resistant lesions. Participants in two separate groups received various combinations of interventions, including narrowband ultraviolet B (NB-UVB) and topical steroid (Clobetasol ointment) as conventional treatments, with fractional CO2 laser or microneedling as add-ons for four symmetrical treatment-resistant lesions. The treatment duration was 16 weeks, followed by observation until six months post-intervention for each patient, and it focused on assessing the percentage of repigmentation, safety, patient satisfaction, and potential adverse effects. Results: The results of the study revealed a significant difference in average efficacy, with treatments involving fractional CO2 laser and microneedling compared with other interventions without them showing a higher percentage of repigmentation. No notable distinction in repigmentation patterns was observed, except for slightly higher marginal repigmentation with microneedling. Side effects, including pain, burning sensation, and erythema, were more frequent, with no significant difference between the groups. Itching and crusting had a significant difference in the two groups. Patient satisfaction levels were comparable, with the first group slightly more than the second. Conclusion: In conclusion, combining NB-UVB and topical steroid therapies with the fractional CO2 laser or microneedling seems to be effective for vitiligo treatment in resistant areas. Attention to variations in patients' characteristics and specific body locations is necessary when applying these modalities. This study provides valuable insights into novel approaches for managing vitiligo and highlights the potential benefits of these innovative treatments in combination with conventional therapy.