The overuse of antibiotics and the emergence of antibiotic-resistant bacterial strains is a global concern. This concern is also of importance in terms of the oral microbiota and the use of antibiotics to deal with oral and dental infections. The aim of this paper was to review the current literature on the indications and use of antibiotics and to make recommendations for their prescription in endodontic patients. Odontogenic infections, including endodontic infections, are polymicrobial, and in most cases, the prescription of antibiotics is empirical. This has led to the increasing use of broad-spectrum antibiotics even in cases where antibiotics are not indicated, such as symptomatic irreversible pulpitis, necrotic pulps and localized acute apical abscesses. In case of discrete and localized swelling, the primary aim is to achieve drainage without additional antibiotics. Adjunctive antibiotic treatment may be necessary in the prevention of the spread of infection, in acute apical abscesses with systemic involvement and in progressive and persistent infections. Medically compromised patients are more susceptible to complication arising from odontogenic infections and antimicrobials have a more specific role in their treatment. Therefore, antibiotics should be considered in patients having systemic diseases with compromised immunity or in patients with a localized congenital or acquired altered defence capacity, such as patients with infective endocarditis, prosthetic cardiac valves or recent prosthetic joint replacement. Penicillin VK, possibly combined with metronidazole to cover anaerobic strains, is still effective in most cases. However, amoxicillin (alone or together with clavulanic acid) is recommended because of better absorption and lower risk of side effects. In case of confirmed penicillin allergy, lincosamides such as clindamycin are the drug of choice.