Chronic inflammation represents a major threat to human health since long‐term systemic inflammation is known to affect distinct tissues and organs. Recently, solid evidence demonstrated that chronic inflammation affects hematopoiesis; however, how chronic inflammation affects hematopoietic stem cells (HSCs) on the mechanistic level is poorly understood. Here, we employ a mouse model of chronic multifocal osteomyelitis (CMO) to assess the effects of a spontaneously developed inflammatory condition on HSCs. We demonstrate that hematopoietic and nonhematopoietic compartments in CMO BM contribute to HSC expansion and impair their function. Remarkably, our results suggest that the typical features of murine multifocal osteomyelitis and the HSC phenotype are mechanistically decoupled. We show that the CMO environment imprints a myeloid gene signature and imposes a pro‐inflammatory profile on HSCs. We identify IL‐6 and the Jak/Stat3 signaling pathway as critical mediators. However, while IL‐6 and Stat3 blockage reduce HSC numbers in CMO mice, only inhibition of Stat3 activity significantly rescues their fitness. Our data emphasize the detrimental effects of chronic inflammation on stem cell function, opening new venues for treatment. Synopsis Chronic inflammation induces HSC expansion and reduces HSC fitness by hyperactivating the IL‐6/Jak/Stat3 signaling pathway. These effects of chronic inflammation on HSCs are mitigated upon inhibition of Stat3. CMO mice, suffering from sterile chronic inflammation, exhibit an expansion of the HSC pool and a reduction of HSC fitness. The CMO environment imprints a myeloid gene signature and imposes a pro‐inflammatory profile in HSCs. Inactivation of the IL‐1β/MyD88 pathway in CMO mice is not sufficient to prevent defects in the HSC compartment. IL‐6 and Jak/Stat3 signaling mediate HSC alterations in CMO mice and inhibition of Stat3 activity rescues HSC function. Chronic inflammation induces HSC expansion and reduces HSC fitness by hyperactivating the IL‐6/Jak/Stat3 signaling pathway. These effects of chronic inflammation on HSCs are mitigated upon inhibition of Stat3.