Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth‐supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3‐domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro‐CT analysis of SH3BP2‐deficient (Sh3bp2^−/− ) mice challenged with ligature‐induced periodontitis revealed that Sh3bp2^−/− mice develop decreased alveolar bone loss (male 14.9% ± 10.2%;​ female 19.0% ± 6.0%) compared with wild‐type control mice (male 25.3% ± 5.8%;​ female 30.8% ± 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM‐Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2‐SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone‐resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS‐9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS‐9973 treatment of bone marrow–derived M‐CSF‐dependent macrophages suppressed tartrate‐resistant acid phosphatase (TRAP)‐positive osteoclast formation with decreased mineral resorption capacity even when GS‐9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2‐SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.