Aim To evaluate the efficacy of selective and nonselective inhibitors of cyclooxygenase‐2 enzymes in the treatment of experimental apical periodontitis induced by bacterial lipopolysaccharide (LPS) in vivo in a mouse model. Methodology Thirty‐six C57BL/6 mice were used. After access cavity preparation, a solution containing E. coli LPS (1.0 µg µL−1) was inoculated into the root canals of the mandibular and maxillary right first molars (n = 72) After 30 days, apical periodontitis was established and the animals were systemically treated with celecoxib, a selective COX‐2 inhibitor (15 mg kg−1), or indomethacin, a nonselective COX‐2 inhibitor (5 mg kg−1), for 7 and 14 days. Blocks containing teeth and bone were removed for histopathological and histometric analyses (haematoxylin and eosin), evaluation of osteoclasts numbers (tartrate‐resistant acid phosphatase enzyme – TRAP) and immunohistochemistry for RANK, RANKL and OPG. Gene expression was performed using reverse transcription and real‐time polymerase chain reaction (qRT‐PCR) for RANK, RANKL, OPG, TRAP, MMP‐9, cathepsin K and calcitonin receptor. Histopathological, histometric, TRAP, immunohistochemistry and qRT‐PCR data were evaluated using Kruskal–Wallis followed by Dunn’s test (α = 0.05). Results Systemic administration of celecoxib for 7 and 14 days prevented periapical bone resorption (P < 0.0001), differently from indomethacin that exacerbated bone resorption at 7 days (P < 0.0001) or exerted no effect at 14 days (P = 0.8488). Celecoxib treatment reduced osteoclast formation in apical periodontitis, regardless of the period of treatment (P < 0.0001 for 7 days and P = 0.026 for 14 days). Administration of celecoxib or indomethacin differentially modulated the expression of genes involved in bone resorption. At 7 days, celecoxib and indomethacin treatment significantly inhibited expression of mRNA for cathepsin K (P = 0.0005 and P = 0.016, respectively) without changing TRAP, MMP‐9 and calcitonin receptor gene expression. At 14 days, celecoxib significantly inhibited expression of mRNA for MMP‐9 (P < 0.0001) and calcitonin receptor (P = 0.004), whilst indomethacin exerted no effect on MMP‐9 (P = 0.216) and calcitonin receptor (P = 0.971) but significantly augmented cathepsin K gene expression (P = 0.001). Conclusions The selective COX‐2 inhibitor celecoxib reduced osteoclastogenic signalling and activity that dampened bone resorption in LPS‐induced apical periodontitis in mice, with greater efficacy than the nonselective inhibitor indomethacin.