Multimorbidity is typically defined as the co-existence of two or more chronic diseases within an individual. Its prevalence is highest among the elderly, with poor quality of life (QoL) being one of the major consequences. This study aims to: (1) understand the relationship between multimorbidity and QoL or health-related quality of life (HRQoL) through systematic literature review; (2) explore the strength of this association by conducting the first meta-analysis on the subject. Following PRISMA, Medline/PubMed, Embase, CINAHL and PsycINFO were searched for studies published through September 1st, 2018. Original studies with clear operationalization of multimorbidity and validated QoL (or HRQoL) measurement were retained. For random-effect meta-analysis, a minimum of three studies with the same multimorbidity tool (e.g. number of diseases or equal comorbidity index) and the same QoL tool were required. Number of diseases was most common and the only measure on which meta-analysis was carried out. The outcome of interest was the linear regression slope between increasing number of diseases and QoL. Heterogeneity was explored with meta-regression. Out of 25,890 studies initially identified, 74 studies were retained for systematic review (total of 2,500,772 participants), of which 39 were included in the meta-analysis. The mean decrease in HRQoL per each added disease, depending on the scale, ranged from: -1.55% (95%CI: -2.97%, -0.13%) for the mental component summary score of pooled SF-36, -12 and -8 scales to -4.37% (95%CI: -7.13%, -1.61%) for WHOQoL-BREF physical health domain. Additional studies considering severity, duration and patterns of diseases are required to further clarify this association.