Objective The goal of root canal therapy is thorough disinfection and obturation of the root canal system in all its dimensions. Success of endodontic treatment is highly related to the elimination of postendodontic pain, tenderness, and swelling. Single-visit endodontic therapy has several advantages such as increased patient acceptance, less overhead costs, and only single time local anesthesia administration is required. Multiple-visit endodontic (MVE) treatment allows the clinician to determine the effect of the therapy on the inflamed tissues and shorter appointments. This in vivo study was undertaken to compare the postoperative incidence of pain, swelling, tenderness, and radiographic evaluation of periapical pathology following single- versus multiple-visit endodontic therapy in vital as well as nonvital teeth. Materials and Methods A total of 60 subjects in the age group of 15 to 50 years were selected for the study. The patients were divided into four groups: • Group 1 (n = 15): Single-visit endodontic (SVE) therapy with vital pulp involvement without periapical rarefaction. • Group 2 (n = 15): SVE therapy of asymptomatic pulpless teeth with periapical rarefaction as observed in radiographic evaluation. • Group 3 (n = 15): MVE of vital pulp involvement without periapical rarefactions. • Group 4 (n = 15): MVE therapy of asymptomatic pulpless teeth with periapical rarefaction as observed radiographically. Access cavity was prepared, working length was taken. Biomechanical preparation was done with Protaper universal rotary file system and obturation was done immediately in single-visit cases. In multivisit cases, Ca (OH)₂ is placed as an intracanal medicament and obturation was done with the help of AH plus sealer and gutta-percha. Postobturation pain levels, swelling, and tenderness on percussion were assessed till 6 weeks. The radiographic parameter was studied till 18 months follow-up. Results Among the different experimental groups, maximum patients in MVE without periapical rarefaction showed no pain according to visual analog scale (VAS) scale, swelling, and tenderness and in SVE with periapical rarefaction showed maximum number of patients reported with pain, tenderness, and swelling. At 4 and 6 weeks postoperatively, patients in all the groups exhibited no pain, swelling, and tenderness to percussion. As periapical rarefaction, healing of periapical lesion was evident in all the patients after 18 months.