Researchers have speculated that sedentary behaviour may reduce health-related quality of life (HRQOL), but the extent to which this is true remains unknown. Our study sought to systematically review and synthesise research on the relationship between sedentary behaviours and HRQOL and to investigate if these relationships are moderated by age, health status, and HRQOL domain. The review was registered with PROSPERO (no. CRD42016036342). We searched six electronic databases. The selection process resulted in including k = 27 original studies; k = 18 were included in a meta-analysis. Data were synthesised twice, using the methods of systematic review and meta-analysis, in order to reduce biases related to a small number of included studies. Both the systematic review and meta-analytical methods indicated that lower levels of sedentary behaviours were associated with higher physical HRQOL (estimate of average effect: r = −.140; 95% CI −.191, −.088). Moderator analyses indicated that associations between the physical HRQOL domain and sedentary behaviours may be similar in strength across age- and health status groups. Causal inferences could not be drawn as most studies were cross-sectional. Concluding, sedentary behaviours were related to better physical HRQOL but not reliably to mental and social HRQOL.