The healthcare burden of patients with multimorbidity may negatively affect their family lives, leisure time and professional activities. This mixed methods systematic review synthesizes studies to assess how multimorbidity affects the everyday lives of middle-aged persons, and identifies skills and resources that may help them overcome that burden. Two independent reviewers screened title/abstracts/full texts in seven databases, extracted data and used the Mixed Methods Appraisal Tool (MMAT) to assess risk of bias (RoB). We synthesized findings from 44 studies (49,519 patients) narratively and, where possible, quantitatively. Over half the studies provided insufficient information to assess representativeness or response bias. Two studies assessed global functioning, 15 examined physical functioning, 18 psychosocial functioning and 28 work functioning. Nineteen studies explored skills and resources that help people cope with multimorbidity. Middle-aged persons with multimorbidity have greater impairment in global, physical and psychosocial functioning, as well as lower employment rates and work productivity, than those without. Certain skills and resources help them cope with their everyday lives. To provide holistic and dynamic health care plans that meet the needs of middle-aged persons, health professionals need greater understanding of the experience of coping with multimorbidity and the associated healthcare burden.