The aim of this systematic review was to compare the clinical performance of calcium hydroxide (Ca(OH)2) as an intracanal medicament alone or combined with other antimicrobial agents. The PICO question was “Is the antibacterial effectiveness of calcium hydroxide paste as an intracanal medication combined with other drugs greater than that of calcium hydroxide paste alone in apical periodontitis?” The study was carried out according PRISMA guidelines and is registered in PROSPERO (CRD42020205741). Searches were performed in the PubMed/MEDLINE, Web of Science and Cochrane databases without publication date restrictions. Inclusion: randomized clinical trials, non-randomized intervention studies, studies including a minimum of 10 patients, studies comparing the use of Ca(OH)2 alone and in combination with other compounds, studies evaluating primary and permanent teeth with apical periodontitis, and studies including teeth not submitted to retreatment. The Cochrane risk-of-bias tool for randomized clinical trials (RoB 2.0) was used to assess the internal validity (risk of bias) of the included studies. A total of 986 articles were retrieved and 12 randomized clinical trials were selected, totaling 499 patients included in the studies. The effectiveness of Ca(OH)2 plus chlorhexidine was similar to that of Ca(OH)2 alone in eight articles, while a better antibacterial effect was reported in three studies. The combination with ciprofloxacin was more effective than the use of Ca(OH)2 alone in the only study that tested this antibiotic. In teeth with asymptomatic apical periodontitis, the effectiveness of the combination of antimicrobial agents with Ca(OH)2 was similar to that of Ca(OH)2 alone.