Purpose: The purpose of this study was to examine the relationship between Physical activity (PA) and health-related quality of life (HRQOL) in a large-scale population of rural adults with chronic disease. Methods: Data for this study came from the CDC's 2015 Behavioral Risk Factor Surveillance System (BRFSS). A total of N=65,492 rural adults 20+ years of age were included in the analysis. The main outcome variable was HRQOL as assessed by the CDC Healthy Days Index. Adults were categorized as "meeting" PA guidelines if they reported 150+ minutes of moderate-intensity PA per week and "not meeting" PA guidelines if they reported less than 150 minutes. Multiple logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) while adjusting for age, sex, race, and income. Results: Rural adults with at least one chronic disease and meeting recommended levels of PA were significantly more likely to report good HRQOL (72.5%; 70.7-74.3) than their less active counterparts (58.1%; 56.4-59.7, p<.001). Those meeting recommended levels of PA had greater odds of good HRQOL regardless of reporting diabetes (OR=1.58; 95% CI: 1.31-1.91), COPD (1.49; 1.20-1.85), cancer (1.79; 1.43-2.22), stroke (1.73; 1.30-2.31), heart disease (1.52; 1.18-1.96), or heart attack (1.68; 1.32-2.15). Additionally, the same increased odds were seen across rural adults reporting 1 (1.59; 1.34-1.88), 2 (1.64; 1.28-2.11), and 3+ (1.52; 1.13-2.05) chronic diseases. Conclusions: Results from this study indicate that meeting recommended levels of PA is strongly associated with optimal levels of HRQOL among rural adults with chronic disease.