Adjunctive use of systemic antibiotics in the treatment of periodontitis and peri-implant infections has for many years been in focus for investigators due to the diversity in clinical picture and variability in treatment response in these conditions. Antimicrobial resistance has emerged as a serious problem worldwide and is one of the most important threats to global health as a result of misuse/overuse of antibiotics. Considering the diversity of the microbiota in the oral cavity and its potential to be a reservoir for antibiotic resistance genes, the misuse of antibiotics can result in negative effects for the individual and its surroundings. With the questionable positive long-term effect of antibiotics in most periodontal infections, use of antibiotics should be restricted and only considered after microbiological diagnostic testing that includes species identification and antibiotic susceptibility testing. For peri-implant infections, there is scarce evidence for the use of systemic antibiotics with no proven effective treatment protocol for good results on a long-term basis.