The postmenopausal period, due to low hormonal concentrations, can exert a negative influence on both periodontitis and osteoporosis evolution. The present study aimed to identify potential clinical and microbiological benefic effects of locally delivered minocycline microspheres (Arestin®) in post-menopausal female patients with moderate and severe periodontitis. Probing depth, clinical attachment levels and bleeding on probing index, along with BANA tests for Porphyromonas gingivalis, Tannerella forsythia, and Treponema denticola, were performed before and at 3 months after a combined treatment of scaling, root planing (SRP), and Arestin® placed in deep periodontal pockets. The association between SRP and Arestin® exerted significant improvements in terms of clinical periodontal parameters, as well as significant reductions in the red complex bacteria detection.