Purpose of Review <p>Emerging evidence indicates that interferons (IFNs) are crucial links between immune activation and skeletal remodeling, highlighting their roles in immune–skeletal interactions. This review highlights the IFN–JAK-STAT (the Janus kinase–signal transducer and activator of transcription) axis as a central signaling hub mediating osteoimmunology and provides an updated overview of its molecular mechanisms and its therapeutic relevance.</p> Recent Findings <p>Interferons play a crucial role in health and disease and consist of three major classes: Type I, II, and III IFNs. All IFNs transduce their signaling through the JAK–STAT pathway. Dysregulated JAK–STAT signaling is a key clinical feature of various pathological conditions, including autoimmune diseases and cancers. Several IFN-targeted and IFN-based therapies have been approved by the FDA for these indications. However, the assessment of skeletal events associated with IFN-related therapeutic strategies remains incomplete, which represents a gap in our knowledge.</p> Summary <p>The role of IFNs in bone metabolism depends on the context and stage, and IFNs can yield opposing effects on skeletal health. A better understanding of the complex regulatory mechanisms downstream of IFN signaling under physiological and pathological conditions is critical for developing targeted interventions to restore the balance between immune response and skeletal health.</p>