Puerto Rico, a U.S. territory, faces numerous challenges that negatively affect public health, including poverty, a fragile health system, insufficient infrastructure, a debt crisis and vulnerability to natural disasters linked to climate change. The impact of these factors on the measure of Health-Related Quality of Life (HRVC) has not been comprehensively evaluated. Only two studies have addressed CVRS, the most recent being in 2011, prior to recent events that could influence public health. The present study aimed to evaluate CVRS and associated sociodemographic and health risk factors in adults living in Puerto Rico in 2019. Prevalences and 95% confidence intervals were used to describe CVRS and its relationship with sociodemographic and health variables in adults who answered the Behavioral Risk Factor Surveillance System (BRFSS) survey (n = 4,944) that year. Multivariable logistic regression models were developed to identify the variables most associated with each of the four central CVRS questions (CVRS-4), expressed as odds of prevalence ratios adjusted for possible confounding factors. Through an exhaustive multivariable analysis, we identified significant risk factors: an increase in the number of chronic conditions, older age and low income, all associated with poor health-related quality of life in Puerto Rican adults. In particular, our findings indicate that people with a greater number of chronic conditions are more likely to report poor quality of life in all four dimensions evaluated. For each additional chronic condition, the chances of reporting: regular or poor general health increased 2.24 times (POR: 2.24, 95% CI: 2.08—2.41), physical impairment 1.93 times (POR: 1.93, 95% CI: 1.78—2.08), mental deterioration 1.90 times (POR: 1.90, 95% CI: 1.78—2.02) and limitation in activities 1.27 times (POR: 1.27, 95% CI: 1.13—1.42). Aging was associated with all domains of poor CVRS, except in the mental health setting, where was higher among the young population (POR: 4.76, 95% CI: 2.4—9.1). This study reveals that the prevalence of poor CVRS has not improved compared to the only previous study conducted in the last decade in Puerto Rico. We also show that poor CVRS is related to the coexistence of multiple chronic conditions in adults in Puerto Rico, possibly a consequence of the deterioration of health services following natural disasters and the island's socioeconomic crisis. The research highlights the need for focused interventions and continuous monitoring of population CVRS to address vulnerable subgroups, especially those with chronic diseases, the elderly and low income, in order to reduce health inequalities in Puerto Rico.