Aim A systematic review to identify which mood and depression measures are valid for use with people with severe cognitive and communication impairments following severe acquired brain injury. Method A systematic search of Cochrane, Web of Science, Ovid, and EBSCOhost was performed in March 2020, July 2021, and September 2022. The search focused on self-report and observer-rated assessment tools used to assess mood, depression, and/or distress in those described as having a severe acquired brain injury. Psychometric properties were extracted using the Consensus-based standards for the selection of health measurement instruments (COSMIN) risk of bias checklist. Qualitative synthesis was performed on extracted patient data. Results Nineteen papers detailing the psychometric properties of 25 measures were included, involving 2,914 participants. Nine papers provided details confirming the severity of participants’ cognitive and communication impairments. The remaining papers described including severely injured participants but provided limited details so that precise level of severity could not be confirmed. Only one paper showed evidence of adequate psychometric properties and included those with severe cognitive impairments in a study of two observer-rated measures, the Stroke Aphasia Depression Questionnaire (10 items) and the Aphasia Depression Rating Scale. Conclusions Due to the exclusion of individuals with severe cognitive and communication consequences following brain injury, no studies using self-report measures showed adequate validity evidence to recommend their use in this population. A small study using two observer-rated scales included those with severe cognitive impairments and showed satisfactory evidence that these measures can be validly used with this population.