Abstract Purpose Evidence suggests that Patient-centred Medical Home (PCMH) model facilitates person-centred care and improves health-related quality of life for patients with chronic illness. This study aims to evaluate changes in health-related quality of life (HRQoL), before and after enrolment into a 12-month integrated care program called ‘WellNet’. Methods This study includes 616 eligible consented patients aged 40 years and above with one or more chronic conditions from six general practices across Sydney, Australia. The WellNet program included a team of general practitioners (GPs) and clinical coordinators (CCs) providing patient-tailored care plans configured to individual risk and complexity. HRQoL was recorded using the validated EuroQol five dimensions five levels (EQ-5D-5L) instrument at baseline and 12 months. Additionally, patients diagnosed with osteoarthritis also reported HRQoL using short versions of Knee and/or Hip disability and osteoarthritis outcome scores (KOOSjr and HOOSjr). A case-series study design with repeated measures analysis of covariance (ANCOVA) was used to assess changes in mean differences of EQ-5D index scores after controlling for baseline covariates. Additionally, backward stepwise multivariable linear regression models were conducted to determine significant predictors of EQ-5D index scores at follow-up. Results Out of 616 patients, 417 (68%) reported EQ-5D scores at follow-up. Almost half (48%) of the WellNet patients reported improved EQ-5D index scores at follow-up. After controlling for baseline covariates, the adjusted mean difference was statistically significant whilst also meeting the bare minimal clinically important difference (MCID) with a change of 0.03 (95% CI 0.01, 0.05). The multivariable regression models determined that baseline EQ-5D scores and positive diagnosis of a respiratory illness were significant predictors of HRQoL at follow-up. There were significant improvements across both KOOS and HOOS assessments, specifically, the pain and symptom scores in both scales met statistical significance in addition to meeting the MCID. Conclusion Patient-tailored chronic disease management (CDM) plans designed by team of GPs and CDM clinical coordinators could lead to better HRQoL among primary care patients.