Objective <p>This study aimed to evaluate the combined and potentially synergistic effects of bioactive glass (BG) and resin infiltration (RI) on the remineralization and resistance to secondary demineralization of orthodontic white spot lesions (WSLs).</p> Methods <p>One hundred twenty human premolars were randomly divided into four groups (<i>n</i> = 30 per group): RI group, BG group, combined RI + BG group, and untreated control group (NT). After creating artificial WSLs, specimens underwent a 4-week remineralization treatment followed by a 2-week secondary demineralization challenge. Surface roughness, microhardness, calcium ion release, and laser scanning confocal microscopy (LSCM) parameters were measured.</p> Results <p>Post-remineralization, the RI + BG group showed the lowest surface roughness, highest microhardness, and most favorable LSCM parameters (TF, FA, AF), with significant differences compared to other groups (<i>p</i> &lt; 0.001). Following secondary demineralization, the RI + BG group maintained the best performance, exhibiting the smallest changes in roughness and microhardness, and the least calcium ion release. The overall efficacy ranking was RI + BG &gt; BG &gt; RI &gt; NT.</p> Conclusion <p>The combination of bioactive glass and resin infiltration exhibited significantly superior remineralization efficacy and resistance to secondary demineralization compared to either treatment alone. This enhanced performance is supported by statistical evidence of synergistic interactions for key mechanical and chemical resistance outcomes, aligning with the observed superior overall effect.</p>