Diabetic osteoporosis is a severe public health concern in the world. Puerarin (PU) is extensively attractive due to its superior bioactivities. In the study, we found that PU protected against streptozotocin (STZ)-induced osteoporotic changes in rats. PU treatment improved STZ-induced diabetes in rats, as evidenced by the reduced serum glucose and insulin levels. PU administration markedly attenuated bone loss and tartarate-resistant acid phosphatase (TRAP) activity in STZ-induced rats. Bone mineral density (BMD) was significantly decreased in diabetic rats, while being prevented by PU. STZ-induced impairments in microarchitecture of femoral tissues were markedly alleviated by PU treatment. In addition, bone-specific alkaline phosphatase (BALP), osteoprotegerin (OPG) and Runt-related transcription factor 2 (Runx2) levels in serum or tibia were improved by PU in STZ-injected rats; however, TRACP isoform 5b (TRACP-5b), carboxy-terminal collagen cross-links (β-CTX) and receptor activator of nuclear factor-κB ligand (RANKL) levels were decreased. Further, PU treatment inhibited inflammation and apoptosis in STZ-treated rats. Additionally, STZ injection increased histone deacetylase (HDAC)-1 and -3 expressions in femoral heads of rats, which were relieved by PU treatment. Notably, both HDAC1 and HDAC3 could enhance osteoporosis in vitro, as proved by the decreased ALP and Runx2 levels and the increased TRAP expression. Inflammation and apoptosis were exacerbated by HDAC1/3 over-expression, which were markedly diminished by PU treatment. In contrast, suppressing HDAC1/3 significantly abrogated fructose (Fru)-elicited inflammation and apoptosis in cells. Collectively, our data illustrated that PU is a potential therapeutic option to prevent diabetic osteoporosis by inhibiting HDAC1/HDAC3 signaling.