This randomized clinical trial aimed to evaluate the effects of intracanal cryotherapy and two intracanal medicaments-calcium hydroxide and metformin-on postoperative spontaneous and percussion pain following root canal treatment in teeth with symptomatic apical periodontitis. In this double-blind, randomized, 2×2 factorial clinical trial, 80 patients with symptomatic apical periodontitis in mandibular premolars were enrolled and randomly assigned to four groups: calcium hydroxide, metformin, cryotherapy plus calcium hydroxide, and cryotherapy plus metformin. All teeth underwent standardized single-visit root canal treatment, and in the cryotherapy groups, final irrigation was performed using sterile saline at 4 °C. Spontaneous pain was assessed preoperatively and daily for 7 postoperative days, while percussion pain was evaluated preoperatively and postoperatively. Pain intensity was recorded using a 100-mm visual analog scale (VAS). Data were analyzed using mixed-effects models for repeated measures and analysis of covariance (ANCOVA) (α = 0.05).