Brain　research　is　a　cutting-edge　topic　but　it　remains　challenging　to　achieve　noninvasive　sensitive　diagnosis　of　brain　diseases.　Lanthanide　nanocrystals　(NCs)　with　near-infrared　II　(NIR-II)　photoluminescence　(PL)　have　shown　great　promise　for　noninvasive　through-skull　highresolution　imaging.　Currently,　it　still　lacks　a　systematic　review　discussing　the　emerging　spectroscopic　and　nanoprobe　engineering　of　NIR-II　luminescent　lanthanide　NCs　for　specific　imaging　of　brain　diseases.　Herein,　we　comprehensively　review　recent　development　of　NIR-II　lanthanide　nanoprobes　for　brain　disease　imaging　in　vivo.　We　first　summarize　luminescence　regulation　strategies　aiming　to　enhance　the　NIR-II　PL　efficiency　of　lanthanide　NCs.　Then,　the　design　strategies　of　lanthanide　nanoprobes　are　introduced　with　the　effort　to　improve　their　brain　delivery　efficacy　and　NIR-II　PL　imaging　specificity　and　sensitivity　in　the　brain.　In　particular,　we　comprehensively　detail　the　latest　tailoring　of　lanthanide　nanoprobes　for　NIRII　PL　imaging　of　brain　diseases　such　as　brain　injuries　and　tumors.　Finally,　we　propose　future　opportunities　and　challenges　in　the　exploration　of　NIR-II　lanthanide　nanoprobes　and　practical　imaging　studies　of　brain　diseases.　This　review　is　anticipated　to　motivate　future　engineering　of　lanthanide　nanoprobes　for　the　diagnosis　and　treatment　of　brain　diseases.