Periapical inflammation occurs as a consequence of insult to the dental pulp in different ways including infection, physical and iatrogenic trauma, and, following endodontic therapy by the damaging effects of root canal filling materials. A problem of endodontic origin is solved mainly by cleaning and disinfecting the root canal system that in turn is dependent on various factors which includes efficient instrumentation, type of irrigant used and the technique applied for irrigation, intracanal dressing, the apical limit of the root canal preparation and obturation, and last but not the least, the quality of the sealer. Moreover, the use of systemic medicines is a great auxiliary in combating pain, inflammation and infection, thus helping to alleviate the clinical symptoms and accelerate the process of healing. The systemic therapy is indicated for treatment of an inflamed and infected pulp can assist in tissue repair by the modulation of the host's immune response. Nevertheless, different therapeutic factors and clinical conditions may interfere in this process of periapical healing. Hence, it is of fundamental importance that the dentist knows about the type of medication to be used in each case and whether systemic therapy is really necessary in a particular case through a comprehensive case evaluation. Hence, this review aims to discuss the success of root canal treatment by presenting the clinical indications of systemic medication application in endodontics. This will aid the professional in achieving more effective results with respect to periapical inflammation.