The complexity of periodontitis, including the complex formation mechanisms and the complex periodontium physiological environment, as well as the complex association with multiple complications, often results in poor therapy effects. Herein, we aimed to design a nanosystem with a controlled release of minocycline hydrochloride (MH) and good retention to effectively treat periodontitis by inhibiting inflammation and repairing the alveolar bone. Firstly, insoluble ion-pairing (IIP) complexes were constructed to improve the encapsulation efficiency of hydrophilic MH in PLGA nanoparticles. Then, a nanogenerator was constructed and combined with a double emulsion method to encapsulate the complexes into PLGA nanoparticles (MH-NPs). The average particle size of MH-NPs was about 100 nm as observed by AFM and TEM, and the drug loading and encapsulation efficiency were 9.59% and 95.58%, respectively. Finally, a multifunctional system (MH-NPs-in-gels) was prepared by dispersing MH-NPs into thermosensitive gels, which could continue to release drug for 21 days in vitro. And the release mechanism showed that this controlled release behavior for MH was influenced by the insoluble ion-pairing complex, PLGA nanoparticles, and gels. In addition, the periodontitis rat model was established to investigate the pharmacodynamic effects. After 4 weeks of treatment, changes in the alveolar bone were assessed by Micro-CT (BV/TV: 70.88%; BMD: 0.97 g/cm; TB.Th: 0.14 mm; Tb.N: 6.39 mm; Tb.Sp: 0.07 mm). The mechanism of MH-NPs-in-gels in vivo was clarified by the analysis of pharmacodynamic results, which showed that insoluble ion-pairing complexes with the aid of PLGA nanoparticles and gels achieved significant anti-inflammatory effects and bone repair capabilities. In conclusion, the multiple controlled-release hydrophilicity MH delivery system would have good prospects for the effective treatment of periodontitis.