BACKGROUND: High-intensity-focused ultrasound (HIFU) has emerged as a noninvasive approach for facial rejuvenation, offering benefits such as collagen synthesis and subcutaneous fat reduction. However, the differential effects of varying HIFU frequencies on specific skin layers remain underexplored. AIMS: To evaluate the histological effects of different HIFU frequencies and correlate these findings with patient-reported outcomes, thereby optimizing clinical applications. PATIENTS/METHODS: Histological analysis was performed on pig skin treated with HIFU at specific depths (2.0, 3.0, 4.5, and 6.0 mm) using the Ultraformer MPT device. Collagen types I and III, elastin fibers, and fat reduction were assessed using immunohistochemistry, Victoria blue staining, and Oil Red O staining. Additionally, 50 Asian female participants aged 30-60 years with skin laxity underwent HIFU treatment. Clinical outcomes were evaluated using standardized photographs, the Global Aesthetic Improvement Scale (GAIS), and a modified Rosenberg Self-Esteem Scale. RESULTS: Histological analysis revealed increased collagen and elastin fiber synthesis and significant fat reduction post-HIFU. Clinical outcomes corroborated these findings, with 85.3% of participants reporting overall satisfaction and 70.6% noting improvements in facial contouring. Self-esteem assessments indicated a positive psychological impact, with 64.7% of participants expressing enhanced confidence. CONCLUSIONS: HIFU treatment at varying frequencies induces significant histological and clinical improvements, demonstrating its efficacy for skin rejuvenation. This study underscores HIFU's dual role in enhancing physical appearance and psychological well-being, supporting its integration into patient-centric aesthetic care.