The co-occurrence of mental and physical chronic conditions is a growing concern and a largely unaddressed challenge in low-and-middle-income countries. This study aimed to investigate the independent and multiplicative effects of depression and physical chronic conditions on health-related quality of life (HRQoL) in China, and how it varies by age and gender. We used two waves of the China Health and Retirement Longitudinal Study (2011, 2015), including 9227 participants aged ≥ 45 years, 12 physical chronic conditions and depressive symptoms. We used mixed-effects linear regression to assess the effects of depression and physical multimorbidity on HRQoL, which was measured using a proxy measure of Physical Component Scores (PCS) and Mental Component Scores (MCS) of the matched SF-36 measure. We found that each increased number of physical chronic conditions, and the presence of depression were independently associated with lower proxy PCS and MCS scores. There were multiplicative effects of depression and physical chronic conditions on PCS (− 0.83 points, 95% CI − 1.06, − 0.60) and MCS scores (− 0.50 points, 95% CI − 0.73, − 0.27). The results showed that HRQoL decreased markedly with multimorbidity and was exacerbated by the presence of co-existing physical and mental chronic conditions.