Abstract: Hydrogel drug delivery systems possess unique structures and properties and hence can be injected and retained in the periodontal pocket for slow and controlled release of medications with antibacterial, anti-inflammatory, and periodontal tissue regeneration-promotional effects. Due to their safety, practicability, and effectiveness, they show great potential in the treatment of periodontitis. In this paper, we gave an overview of hydrogel drug delivery systems in the treatment of periodontitis, summing up the classification and forms of the drugs delivered and the strengths and weaknesses of common types of hydrogel matrixes. In addition, we discussed properties required for hydrogel drug delivery systems applicable in the treatment of periodontitis, including a certain level of viscosity, suitable degradation cycle, and temperature sensitivity. Finally, we summarized the stimulus responsiveness types of hydrogel drug delivery systems applicable in the treatment of periodontitis, including pH-responsiveness, enzyme-responsiveness, reactive oxygen species-responsiveness, light-responsiveness, and sugar-responsiveness. In the future, researchers should make further investigation into the clinical efficacy of hydrogel drug delivery systems and promote their translation into clinical applications. Additionally, hydrogel drug delivery systems carrying biologic drugs could be further investigated to promote advancement in the field of periodontal tissue regeneration. Furthermore, the response sources, realization strategies, and safe preparation methods of smart hydrogel drug delivery systems should also be further clarified and explored to achieve drug delivery of better efficiency and safety. In addition to drug delivery, hydrogel matrixes with medicinal values also show great promises.