Background: In dental avulsion, delayed replantation usually has an uncertain prognosis. After tooth replantation, complex inflammatory responses promote a return to periodontal tissue homeostasis. Various types of cytokines are produced in the inflammatory microenvironment, and these cytokines determine the periodontal tissue response. This study aims to conduct in-depth research on developing a novel root canal medicament, which employed methylcellulose hydrogel as a carrier system and was loaded with clindamycin, acetazolamide and triamcinolone, to determine its triple action of antibacterial, anti-inflammatory and anti-resorptive capabilities in delaying tooth replantation and to preliminarily explore its potential mechanisms of action. Methods: The release concentration of the paste from human extracted root apices was determined using UV-spectrophotometry. The cytotoxicity of corresponding drug concentrations on HPDLFs (human periodontal ligament fibroblasts) was assessed on days 1, 3, 5, and 7 using the CCK-8 (cell counting kit-8) assay. The antibacterial activity against Fusobacterium nucleatum (F. nucleatum) was measured using the agar diffusion method. The gene and protein expression of inflammatory factors (IL-1β (interleukin-1β), IL-6 (interleukin-6), TNF-α (tumor necrosis factor-α) and bone metabolism molecules (RANK (Receptor Activator of Nuclear Factor-κB), RANKL (Receptor Activator of Nuclear Factor-κB Ligand), OPG (Osteoprotegerin)) in HPDLFs stimulated with Escherichia coli (E. coli) lipopolysaccharide were determined by ELISA (enzyme-linked immunosorbent assay) and RT-qPCR (real-time quantitative polymerase chain reaction), respectively. Furthermore, the rat delayed replantation tooth models were established and the resorption of incisors was analyzed by micro-CT (micro-computed tomography) after 60 days. The degree of root inflammation and resorption was evaluated by hematoxylin-eosin (HE) staining, and the expression of RANKL/OPG was assessed by immunohistochemical staining. Results: The novel paste showed sustained slow release in root canals for 60 days. In vitro, the experiments demonstrated good cell compatibility and antibacterial activity (p < 0.01). The paste suppressed the expression of IL-1β, IL-6 and TNF-α, and down-regulated the RNA and protein levels of RANKL and OPG in HPDLFs stimulated by E. coli (p < 0.05). In vivo experiments revealed that the novel paste down-regulated the expression of RANKL and OPG, effectively preventing inflammatory root resorption in rat delayed replantation teeth (p < 0.05). Conclusion: The novel paste can inhibit inflammatory root resorption by modulating the RANKL/RANK/OPG signaling pathway and has the potential to be used as an intracanal medicament for root canal treatment in delayed replantation teeth.