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　high-resolution　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　NIR-II　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.　©　2023　Elsevier　B.V.