Objective The challenges posed by people living with multiple chronic conditions are unique for people with dementia and other significant cognitive impairment. There have been recent calls to action to review the existing literature on co‐occurring chronic conditions and dementia in order to better understand the effect of cognitive impairment on disease management, mobility, and mortality. Methods This systematic literature review searched PubMed databases through 2011 (updated in 2016) using key constructs of older adults, moderate‐to‐severe cognitive impairment (both diagnosed and undiagnosed dementia), and chronic conditions. Reviewers assessed papers for eligibility and extracted key data from each included manuscript. An independent expert panel rated the strength and quality of evidence and prioritized gaps for future study. Results Four thousand thirty‐three articles were identified, of which 147 met criteria for review. We found that moderate‐to‐severe cognitive impairment increased risks of mortality, was associated with prolonged institutional stays, and decreased function in persons with multiple chronic conditions. There was no relationship between significant cognitive impairment and use of cardiovascular or hypertensive medications for persons with these comorbidities. Prioritized areas for future research include hospitalizations, disease‐specific outcomes, diabetes, chronic pain, cardiovascular disease, depression, falls, stroke, and multiple chronic conditions. Conclusions This review summarizes that living with significant cognitive impairment or dementia negatively impacts mortality, institutionalization, and functional outcomes for people living with multiple chronic conditions. Our findings suggest that chronic‐disease management interventions will need to address co‐occurring cognitive impairment. Copyright © 2017 John Wiley & Sons, Ltd.