Objectives Oral health-related quality of life (OHRQoL) is an important health indicator not only for individuals but also for oral health care providers to treat a person holistically. Previous studies focused on OHRQoL do not provide comprehensive knowledge regarding low-income patients in the United States, many of whom have chronic health conditions that can affect their oral health. The purpose of this study is to examine factors associated with OHRQoL among low-income, uninsured patients of safety-net providers, which provide free or reduced fee medical and/or dental care to underserved populations. Methods Uninsured patients (N = 584) participated in a self-administered survey in May and June 2016 at a safety-net clinic in the United States serving a low-income uninsured population, which provides limited oral health care services. This study used cross-sectional design and a nonprobability sample. The dependent variable was OHRQoL measured using the Oral Health Impact Profile-14. Chi square tests, Analysis of Variance tests, and multiple regression were used for statistical analysis. Results Higher levels of dental care neglect and lower frequency of oral hygiene practice were associated with lower levels of OHRQoL (P < 0.01). Participants utilizing a diabetes clinic reported better OHRQoL than those who were not patients of a diabetes clinic (P < 0.05). US born English speakers had worse general health and OHRQoL compared to non-US born English speakers and Spanish speakers (P < 0.01). Conclusions An intervention to remedy dental neglect is recommended to improve OHRQoL among uninsured safety-net patients.