The upregulation of CD74, a chaperone involved in MHC-II antigen processing, has been mostly interpreted as indicative of antigen presentation in multiple brain disorders. However, CD74 expression has also been described in cancer cells across multiple tumor types and in the tumor microenvironment, notably in glioma. Here, we found that the presence of CD74+ microglia/macrophages, which was induced by increased levels of interferon gamma in brains affected by metastases, did not relate to its canonical pathway. Instead, the alternative function of CD74 as a cytokine receptor was pivotal. Proliferating cancer cells produced high levels of the ligand MIF that bound the CD74 receptor and induced its translocation to the nucleus where it activated a NF-κB-dependent program that promoted metastatic progression. In patients, a CD74 signature was associated with more aggressive progression of brain metastatic disease, while it had no clinical correlation with the matched primary tumor. Interestingly, a pan-disease non-canonical and clinically relevant signature derived from the CD74+ myeloid population was identified that occurred in additional brain disorders including Alzheimer's disease and multiple sclerosis. The brain-penetrant drug ibudilast, which prevents the binding of MIF to CD74, decreased brain metastasis in experimental models in vivo and in patient-derived organotypic cultures ex vivo in a primary tumor-agnostic manner. These findings suggest that MIF/CD74-induced reprogramming of myeloid cells in brain disorders is a vulnerability that could be exploited therapeutically against brain metastases, and possibly other brain disorders.