Objectives <p>This systematic review and meta-analysis (SRM) evaluated the effect of incorporating calcium-based bioactive agents in bleaching gels on dental structure preservation and whitening efficacy.</p> Methods <p>A comprehensive search was conducted across databases up to November 2024. Two independent reviewers screened and selected clinical trials and in vitro studies evaluating the effects of calcium-based bioactive agents in bleaching gels, following predefined PICO criteria. Data extraction and quality assessments were performed using the Cochrane Collaboration tool and Joanna Briggs Institute Critical Appraisal Tools. Meta-analyses were conducted with RevMan software, using the mean difference as the effect measure.</p> Results <p>Out of 4,289 articles identified, 56 met the inclusion criteria, consisting of 50 in vitro studies and 6 clinical trials. The agents evaluated included calcium ions, calcium gluconate, amorphous calcium phosphate, CPP-ACP, and calcium polyphosphate. Overall, all agents reduced the adverse effects associated with bleaching therapy, such as minimizing changes in the mechanical and morphological properties of enamel, reducing transamelodentinal diffusion, and clinically decreasing tooth sensitivity. None of the calcium-based agents interfered with the bleaching effect. In short, the studies demonstrated a low risk of bias.</p> Conclusions <p>Calcium-based agents incorporated into bleaching gels reduced bleaching-induced changes in dental tissues and demonstrated clinical aesthetic results comparable to conventional gels. However, further clinical trials are needed to optimize formulations, application protocols, and confirm the findings of this study.</p> <p>Clinical relevance.</p> <p>This SRM provides evidence that these agents offer additional benefits by enhancing the biocompatibility and safety of whitening therapy over conventional treatments, guiding clinicians in material selection for whitening procedures.</p>