Background: Fluoride-releasing restorative materials such as glass ionomer cements (GIC), resin-modified GICs (RMGIC), compomers, and giomers play a vital role in caries prevention. However, their fluoride release kinetics, mechanical strength, and clinical performance vary significantly. A systematic comparative evaluation using standardized laboratory methods and short-term clinical assessment can provide valuable clinical guidance. Aim: To compare fluoride release, mechanical properties, microleakage, and short-term clinical performance of four commercially available fluoride-releasing restorative materials. Materials & Methods: This study consists of two arms: an in vitro study using extracted human premolars (n = 10 per group) and a 2- year randomized controlled clinical trial (n = 78 restorations per group after sample size calculation). Four restorative materials were evaluated: (A) conventional GIC, (B) RMGIC, (C) compomer, and (D) giomer. Fluoride release was measured at 1, 3, 7, 14, 30, 60, and 90 days using an ion-selective electrode (ISE). Mechanical properties were assessed using Vickers microhardness, flexural strength (ISO 4049), and microleakage scoring after thermocycling. In the clinical arm, Class V and small Class I restorations were followed up at 6, 12, and 24 months. Statistical analysis included ANOVA, chi-square tests, and Kaplan–Meier survival analysis with significance at p < 0.05. Results: Conventional GIC showed the highest initial fluoride burst but lowest mechanical strength. Compomers demonstrated superior mechanical properties but the least fluoride release. RMGIC and giomer showed balanced performance. Clinically, giomer and RMGIC demonstrated the highest retention at 24 months (90–92%), whereas GIC showed the lowest (72%). A moderate inverse correlation was found between fluoride release and secondary caries incidence.

Conclusion: No single material was superior in all parameters. RMGIC and giomer showed balanced properties, making them suitable for both preventive and restorative purposes. Material selection should depend on clinical indication and caries risk profile.