Health related quality of life (HRQoL) is a subjective appreciation of how personal characteristics and health influence well-being. This cross-sectional analysis aimed to quantitatively measure the influence of dietary, lifestyle, and demographic factors on HRQoL. A sub-sample of the Seguimiento Universidad de Navarra (SUN) Project, a Mediterranean cohort, was analyzed (n = 15,674). Through self-administered questionnaires the relationship between HRQoL and dietary patterns (Mediterranean-diet (MedDiet) and provegetarian food pattern (FP) assessment), lifestyles (sleeping hours, physical activity) and demographic characteristics were measured. Multivariate linear regression and flexible regression models were used to estimate the pondered effect of personal factors on Short Form-36 (SF-36) scores. Coefficients for MedDiet and provegetarian scores (beta-coefficient for global SF-36 score: 0.32 (0.22, 0.42); 0.09 (0.06, 0.12) respectively for every unit increase), physical activity (beta: 0.03 (0.02, 0.03) for every metabolic equivalent of task indexes (MET)-h/week) had a positive association to HRQoL. The female sex (beta: -3.28 (-3.68, -2.89)), and pre-existing diseases (diabetes, beta: -2.27 (-3.48, -1.06), hypertension beta: -1.79 (-2.36, -1.22), hypercholesterolemia beta: -1.04 (-1.48, -0.59)) account for lower SF-36 scores. Adherence to MedDiet or provegetarian FP, physical activity and sleep are associated with higher HRQoL, whereas the female sex, "other" (versus married status) and the presence of chronic diseases were associated with lower SF-36 scores in this sample.