Objective: To investigate the effects of zoledronic acid (ZA) on periodontal indices, serum inflammatory markers, and bone metabolism in postmenopausal osteoporosis (PMO) patients with periodontitis (PD). Methods: A total of 113 PMO+PD cases were recruited between May 2021 and February 2024. Fifty-two cases in the control group received standard therapy, while 61 cases in the observation group were treated with ZA. Therapeutic efficacy, periodontal indices (attachment loss [AL], probing depth [PD], and gingival bleeding index [GBI]), serum inflammatory markers (interleukin-1(3 [IL-1(3], tumor necrosis factor-alpha [TNF-alpha], and C-reactive protein [CRP]), bone metabolism markers (N-terminal midfragment of osteocalcin [N-MID], beta-CrossLaps [(3-CTx], and human calcitonin [hCT]), safety (fever, constipation, muscle soreness), and bone mineral density (BMD) at the lumbar spine and proximal femur were analyzed. A multivariable binary logistic regression model was used to determine factors influencing therapeutic efficacy. Results: The observation group demonstrated significantly better therapeutic outcomes than the control group. Treatment type was identified as an independent factor influencing efficacy. In the observation group, AL, PD, GBI, IL-1(3, TNF-alpha, CRP, N-MID, and (3-CTX levels were significantly reduced post-intervention compared to pre-intervention levels and the control group (all P<0.05), with no significant inter-group differences in hCT levels or adverse event rates (both P>0.05). BMD in the lumbar spine and proximal femur improved significantly in the observation group compared to the control group (both P<0.05). Conclusions: ZA positively impacts periodontal health, reduces serum inflammation, and enhances bone metabolism in PMO patients with PD.