Photodynamic　therapy　(PDT)　has　been　considered　as　a　promising　and　noninvasive　strategy　for　clinical　cancer　treatment.　Nonetheless,　building　a　smart　＂off-on＂　theranostic　PDT　platform　to　spatiotemporally　control　the　generation　of　reactive　oxygen　species　in　the　PDT　treatment　still　remains　challenging.　Here,　we　have　rationally　developed　photoswitching　upconversion　nanoparticles　(UCNPs)　with　orthogonal　emissive　properties　in　response　to　two　distinct　near-infrared　(NIR)　emissions　at　808　and　980　nm,　i.e.,　red　emission　with　980　nm　excitation　and　green　emission　with　808　nm　excitation.　Unlike　traditional　photoswitching　UCNPs,　these　specially　designed　core-shell-shell　structured　UCNPs　do　not　require　compli-　cated　multilayer　doping　as　their　red　and　green　upconversion　luminescence　both　originate　from　the　same　activator　Er3+　ions　in　the　core　structure.　As　a　proof　of　concept,　we　have　demonstrated　the　capability　of　these　orthogonal　emissive　UCNPs　for　imaging-guided　PDT　in　a　real-time　manner,　where　the　red　emission　excited　by　980　nm　light　is　used　to　trigger　PDT　and　the　green　emission　with　808　nm　excitation　is　to　diagnose　and　monitor　the　therapeutic　treatment.　Our　study　suggests　that　such　specially　designed　UCNPs　with　orthogonal　emissions　hold　great　promise　for　NIR　light-targeted　and　imaging-guided　therapy　under　precisely　spatiotemporal　control.