Background: Low bone mineral density (BMD) is the hallmark of osteoporosis, postmenopausal women are more likely to have microarchitectural deterioration and fracture risks. This study aimed to determine the relationship between serum creatinine (sCr) levels and osteoporosis in women who are early postmenopausal. Methods: There were 335 early postmenopausal women (age 40–60 years) in Dongguan, China, included in this cross-sectional study. BMD in the lumbar spine, femoral neck, and trochanter was measured using dual-energy X-ray absorptiometry (DXA) and assessed using multivariable-adjusted logistic regression models based on sCr levels obtained during the first DXA examination. Results: Without osteoporosis patients had significantly higher sCr levels than osteoporosis patients. Overall, 75 (22.4%) participants (age, 51.3 \pm 5.2 years) had osteoporosis. The median sCr level was 55.9 \pm 9.6 µmol/L (range, 29.0–94.0 µmol/L). sCr levels increased by 1 µmol/L, while the risk of osteoporosis decreased by 4% (odds ratio [OR], 0.96; 95% confidence interval [95% CI], 0.93–0.99), when menopause duration, menopause rating scale, body mass index, smoking habits, alcohol consumption, activity status, serum uric acid, and serum urea nitrogen were considered. Participants in the highest sCr quantile were at low risk for osteoporosis compared with those in the lowest quantile (OR, 0.46; 95% CI, 0.22–0.94). Based on subgroup and sensitivity analyses, this association remained stable. Conclusions: The sCr levels of early postmenopausal women are negatively associated with BMD, independent of age, menopause duration, and serum uric acid levels. As a marker of bone health, sCr may be a valuable indicator of skeletal muscle mass and provide evidence for future osteoporosis markers.