Background <p>Health-related Quality of life (HRQoL) is associated with multimorbidity, but the underlying mechanisms remain poorly understood. This study aimed to explore the association between multimorbidity and HRQoL, focusing on intrinsic capacity (IC) as a mediator.</p> Methods <p>This cross-sectional study was conducted under the World Health Organization (WHO) Integrated Care for Older People (ICOPE) pilot program in Lianyungang, China, between April and July 2024. Multimorbidity was classified by clinicians’ experience, Charlson Comorbidity Index, and Cumulative Illness Rating Scale for Geriatrics. HRQoL was assessed using EQ-5D-3L. IC was assessed based on the WHO’s guidelines for ICOPE. Logistic regression was used to calculate the correlation between multimorbidity and HRQoL. Mediation model was further constructed to assess the mediating role of IC.</p> Results <p>This study recruited 468 adults aged ≥ 60 years (207 males [44.2%]). In logistic regression, the risk of reduced HRQoL increased by 22% per additional condition (adjusted for gender, age, IC, marital status, education, nursing home resident status). Specifically, compared to Q1 (multimorbidity number = 0), the risk of poor HRQoL increased by 148% (95% CI: 1.39–4.43, <i>p</i> = 0.002) in Q2 (number = 1), 172% (95% CI: 1.48–5.01, <i>p</i> = 0.001) in Q3 (number = 2–3), and 194% (95% CI: 1.57–5.50, <i>p</i> &lt; 0.001) in Q4 (number ≥ 4), respectively. Additionally, mediation analysis showed that IC mediated 25.90% of the multimorbidity-HRQoL association (<i>p</i> &lt; 0.001).</p> Conclusion <p>Our findings suggest that multimorbidity was a risk factor for poorer HRQoL. IC was a useful indicator for identifying HRQoL and mediated the multimorbidity-HRQoL association.</p>