Periodontal disease is an oral infectious and inflammatory disease caused by microorganisms that determine the host-mediated destruction of soft and hard periodontal tissues, which ultimately leads to tooth loss. Periodontitis affects a large part of the population, with various degrees of severity. Treatment consists of etiologic therapy: the removal of biofilm through mechanical debridement plus microbial elimination by supplementary measures. Antibiotic administration, either systemically or through local delivery, has been shown to improve clinical outcomes after mechanical periodontal treatment. Clindamycin is a lincosamide with a broad spectrum, being active against aerobic, anaerobic, and β-lactamase-producing bacteria. This antibiotic offers several advantages and some disadvantages and has been used in periodontal treatment both systemically and locally with various degrees of success. Among the properties that recommend it for periodontal treatment is the bacteriostatic effect, the inhibition of bacterial proteins synthesis, the enhancement of neutrophil chemotaxis, phagocytosis and the oxidative burst-oxidative stress storm. Furthermore, it is easily absorbed at the level of oral tissues in a considerable amount. This substantial tissue penetration, especially inside the bone, is synergistic with a stimulating effect on the host immune system. The aim of this review is to explore the applicability of this antibiotic agent and to evaluate its antimicrobial potential and limitations at the level of the oral biofilm associated with periodontal disease.