Ex vivo MPM imaging of intrinsic two photon excited fluorescence (TPEF) was performed on mouse splenic, lung, lymph and brain tissue of both wild type and sickle cell disease (SCD) mouse model. Distinct morphological and spectral features associated with SCD are demonstrated and discussed. This work provides a basis for further monitoring investigations of SCD in live animals as a means to gain insight into the mechanisms of the disease impact on immune dysregulation and organ malfunction, which is not well understood.