ABSTRACT Osteoporosis is a disorder of decreased bone mass, microarchitectural deterioration, and fragility fractures. Ganoderma lucidum has been reported to have a variety of pharmacological activities, including immune regulation, anti‐inflammation, antioxidation, sedative hypnosis, blood sugar and lipid regulation, and so on. However, the effective ingredients and the underlying mechanism of Ganoderma lucidum against osteoporosis are rarely clarified. Ganoderic acid A (GA‐A), a triterpenoid, is one of the main components of Ganoderma lucidum. Our previous preliminary bioinformatic study found that it may affect bone metabolism, and it has been reported that GA‐A has anti‐osteoporosis potential via regulating MC3T3‐E1 cells' osteogenic differentiation activity. Therefore, the aim of this study is to investigate the effects of Ganoderic acid A in preventing osteoporosis and uncover the potential mechanisms. In vivo, the 8‐week‐old C57BL/6J female mice were used to establish the osteoporosis model by ovariectomy (OVX). Two cell lines, MC3T3‐E1 cells and primary osteoblasts, were used and induced with hydrogen peroxide (H 2 O 2 ) to the state of oxidative stress in osteoporosis in vitro. We showed that Ganoderic acid A could inhibit OVX‐induced bone loss in a dose‐dependent manner and promote H 2 O 2 ‐induced osteogenic differentiation of primary osteoblasts and MC3T3‐E1 cells. The mechanism‐related signaling pathways were identified by network pharmacology screening and verified by bioinformatics. Results predicted that the target of Ganoderic acid A might be PIK3CA. Mechanistically, we found that PIK3CA activated the Akt receptor, then inhibited the expression of TWIST1 in the osteoblasts to up‐regulate the protein expression of the osteogenic‐related markers. Our results suggested that Ganoderic acid A could prevent OVX‐induced osteoporosis and promote H 2 O 2 ‐induced osteogenic differentiation of primary osteoblasts and MC3T3‐E1 cells. Ganoderic acid A might play an important role in the prevention of osteoporosis by modulating the PIK3CA/p‐Akt/TWIST1 signaling pathway.