Osteoarthritis (OA) is a common degenerative disease of articular cartilage, and there is currently no effective treatment. Baicalein, a flavonoid extracted from plants of the Scutellaria genus, has frequently been used in the past as an anti-inflammatory and anti-allergic therapy. This study investigated the effect of baicalein on OA development. For in vivo study, a destabilization of the medial meniscus (DMM)-induced OA model was established in 8-week-old wild-type (WT) and AMPKα-knockout (KO) mice, while an in vitro study was performed using chondrocytes in an OA microenvironment induced by interleukin-1β (IL-1β) exposure. We found that baicalein alleviated OA development in vivo and exerted a chondroprotective effect in vitro by suppressing chondrocyte ferroptosis. Baicalein reduced OA-related pain sensitivity by inhibiting ferroptosis of chondrocytes in OA mice. Baicalein also facilitated AMPK holoenzyme assembly, stability, and activity and suppressed ferroptosis by inducing AMPKα phosphorylation in chondrocyte. In addition, AMPKα preserved nuclear factor erythroid 2-related factor 2(Nrf2) abundance in chondrocytes and induced Nrf2 into nucleus by promoting Keap1 degradation. Meanwhile, Nrf2 increased expression of heme oxygenase-1(HO-1) to inhibit chondrocyte lipid ROS. Taken together, these results showed that baicalein alleviated OA development by improving the activity of AMPK/Nrf2/HO-1 signaling to inhibit chondrocyte ferroptosis, revealing baicalein to be a potential therapeutic strategy for OA.