Objectives: The misuse of pain relievers has been linked to mental and behavioral disorders. This study aims to determine the associations between pain-reliever misuse, severe psychological distress (SPD), suicidal ideation, and difficulties in performing daily activities. Additionally, it seeks to identify the socio-demographic factors associated with pain-reliever misuse across different racial and ethnic groups. Methods: This cross-sectional study utilizes data from the 2022 United States National Survey on Drug Use and Health (NSDUH). Participants were categorized into four groups: non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic/Latino (Hispanic), and Other (American Indian, Alaska Native, Asian, Native Hawaiian or other Pacific Islanders, and two or more races) groups. Comparisons were made between individuals regarding pain-reliever misuse, socio-demographic characteristics, SPD, suicidal thoughts, and World Health Organization Disability Assessment Schedule (WHODAS) scores, using Rao–Scott Chi-square tests. Stepwise multivariable logistic regression analyses were conducted to identify socio-demographic factors associated with pain-reliever misuse. Results: The study included 45,451 participants, with 27,551 (62.00 wt%) identified as NHW, 5186 (11.98 wt%) as NHB, 7795 (17.15 wt%) as Hispanic, and 4919 (8.87 wt%) as other racial and ethnic groups. The rate of pain-reliever misuse was 2.90% among NHWs, 3.40% among NHBs, 3.61% among Hispanics, and 2.05% among individuals of other races and ethnicities (p = 0.043). Among those who misused pain relievers, a significantly higher proportion experienced SPD (36.00% vs. 14.05%), suicidal thoughts (15.51% vs. 4.91%), and difficulties in performing daily activities (73.77% vs. 52.84%) compared to those who did not misuse pain relievers (p < 0.001). Socio-demographic factors associated with a lower risk of misuse included being female (AOR = 0.80, 95% CI 0.67–0.95, p = 0.013), being employed (AOR = 0.66, 95% CI 0.48–0.90, p = 0.010), and having a college or higher education (AOR = 0.54, 95% CI 0.37–0.79, p = 0.002). Conclusions: The prevalence of pain-reliever misuse varies across racial and ethnic groups, with Hispanic individuals demonstrating the highest rates of misuse. Pain-reliever misuse is strongly associated with SPD, suicidal thoughts, and impaired daily functioning. Socio-demographic factors are crucial in predicting the likelihood of pain-reliever misuse. These findings highlight the importance of culturally tailored prevention strategies and public health policies aimed at mitigating misuse, especially among vulnerable populations.