Background: Dental caries remains a predominant chronic disease among school-aged adolescents worldwide despite advances in preventive dentistry. Fluoride varnish and silver diamine fluoride represent two topical fluoride-based interventions with demonstrated anticaries efficacy; however, direct comparative evidence evaluating their caries-preventive effectiveness in adolescent permanent dentitions remains limited. Objective: This randomized controlled clinical trial aimed to compare the caries-preventive efficacy of 5% sodium fluoride varnish versus 38% silver diamine fluoride applied semiannually over an 18-month period among school-aged adolescents. Methods: A total of 360 adolescents aged 12–15 years with at least one sound first permanent molar at high caries risk were randomly allocated to three groups: fluoride varnish (FV, n = 120), silver diamine fluoride (SDF, n = 120), and placebo control (n = 120). Applications were performed at baseline, 6, and 12 months. Caries assessments using ICDAS-II criteria were conducted at baseline and 18 months by calibrated examiners blinded to group allocation. The primary outcome was new caries incidence on permanent teeth. Results: At 18 months, the mean number of new carious surfaces was significantly lower in the SDF group (0.82 ± 0.94) and FV group (1.24 ± 1.12) compared with the control group (2.47 ± 1.68) (p < 0.001). SDF demonstrated a caries-preventive fraction of 66.8% compared with 49.8% for FV, with the difference between SDF and FV reaching statistical significance (p = 0.003). The proportion of participants remaining caries-free was highest in the SDF group (58.3%) compared with the FV (43.3%) and control (22.5%) groups (p < 0.001). However, tooth staining was significantly more prevalent in the SDF group (72.5%) than in the FV group (3.3%) and the control group (0%) (p < 0.001). Conclusion: Both silver diamine fluoride and fluoride varnish significantly prevented new caries development in adolescents compared with placebo; however, SDF demonstrated superior caries-preventive efficacy. The aesthetic concern of tooth staining associated with SDF use requires careful consideration in adolescent populations.