4-Phenylbutyric acid (4-PBA) has been used clinically to treat urea cycle disorders and is known to be an inhibitor of endoplasmic reticulum (ER) stress. We hypothesized that 4-PBA attenuates inflammatory bone loss by inducing autophagy, a process that is frequently accompanied by ER stress. Micro computerized tomography analysis showed that 4-PBA attenuated LPS-induced bone loss in mice. The increased area of TRAP-positive osteoclasts (OCs) and serum level of collagen type I fragments in lipopolysaccharide (LPS)-treated mice were also decreased when 4-PBA was administered, suggesting a protective role of 4-PBA in OCs. In vitro, 4-PBA significantly reduced OC area without affecting the number of OCs induced by LPS and decreased bone resorption upon LPS stimulation. LPS-induced autophagy was attenuated by 4-PBA in OCs, as demonstrated by reduced LC3II accumulation, increased p62 level, and reduction in AVO-containing cells. Silencing of autophagy-related protein 7 attenuated the effects of 4-PBA on OC size and fusion. Moreover, 4-PBA reduced nuclear factor-κB (NF-κB) DNA binding upon LPS stimulation of OCs. Inhibition of NF-κB activation diminished the inhibitory effect of 4-PBA on LPS-stimulated changes in LC3II level, OC area, and OC fusion, implying that the effects of 4-PBA on OCs are due at least in part to inhibition of NF-κB. These data demonstrate that 4-PBA attenuates LPS-induced bone loss by reducing autophagy in OCs. Our data highlight the therapeutic potential of 4-PBA for ameliorating inflammatory bone loss.