Changes between diet quality and health-related quality of life (HR-QoL) over 12 years were examined in men and women, in 2844 adults (46 % males; mean age 47 center dot 3 (sd 9 center dot 7) years) from the Australian Diabetes, Obesity and Lifestyle study with data at baseline, 5 and 12 years. Dietary intake was assessed with a seventy-four-item FFQ. Diet quality was estimated with the Dietary Guideline Index, Mediterranean-Dietary Approaches to Stop Hypertension Diet Intervention for Neurological Delay Index (MIND) and Dietary Inflammatory Index. HR-QoL in terms of global, physical component summary (PCS) and mental component summary (MCS) was assessed with the Short-Form Health Survey-36. Fixed effects regression models adjusted for confounders were performed. Mean MCS increased from baseline (49 center dot 0, sd 9 center dot 3) to year 12 (50 center dot 7, sd 9 center dot 1), whereas mean PCS decreased from baseline (51 center dot 7, sd 7 center dot 4) to year 12 (49 center dot 5, sd 8 center dot 6). For the total sample, an improvement in MIND was associated with an improvement in global QoL (beta = 0 center dot 28, 95 % CI (0 center dot 007, 0 center dot 55)). In men, an improvement in MIND was associated with an improvement in global QoL (beta = 0 center dot 28, 95 % CI (0 center dot 0004, 0 center dot 55)). In women, improvement in MIND was associated with improvements in global QoL (beta = 0 center dot 62 95 % CI (0 center dot 38, 0 center dot 85)), MCS (beta = 0 center dot 75, 95 % CI (0 center dot 29, 1 center dot 22)) and PCS (beta = 0 center dot 75, 95 % CI (0 center dot 29, 1 center dot 22)). Positive changes in diet quality were associated with broad improvements in HR-QoL, and most benefits were observed in women when compared to men. These findings support the need for strategies to assist the population in consuming healthy dietary patterns to lead to improvements in HR-QoL.