Black men who have sex with men (MSM) engaged in sex work (BMSM-SW) experience elevated HIV and sexually transmitted infection (STI) prevalence. Further, BMSM-SW have been shown to have higher rates of syndemic psychosocial health conditions which contribute to HIV risk behavior and incidence, and poorer care outcomes than other groups of men who have sex with men. However, syndemic perspectives have not been applied to understanding past-year STI burden among BMSM-SW in the U.S. Sexually active Black MSM ≥ 18 years old were recruited from Black Pride events in six U.S. cities (n = 4421) between 2014 and 2017. Multivariable logistic regressions assessed correlates of past-year sex work engagement; whether BMSM-SW had higher odds of syndemic conditions; and whether BMSM-SW had higher odds of self-reported, past-year STI diagnoses. Structural equation models assessed relationships between sex work engagement, syndemic conditions, and STI controlled for sociodemographics and number of sexual partners. A total of 254 (5.7%) Black MSM reported past-year sex work, of whom 45.3% were HIV positive. BMSM-SW were significantly more likely to be Hispanic, to report past-year bisexual behavior, and to report annual income < $10,000. In multivariable models, BMSM-SW were significantly more likely to report intimate partner violence, assault victimization, polydrug use, and depression symptoms; they were also more likely to report past-year gonorrhea, chlamydia, and syphilis. Syndemic conditions mediated the relationship between past-year sex work and past-year STI burden, constituting a significant indirect effect. BMSM-SW in the U.S. face severe biopsychosocial health disparities. Interventions developed for BMSM engaged in sex work are lacking. Our results suggest that interventions containing safer sex work education and sex-positive biobehavioral HIV/STI prevention alongside substance use, mental health, employment, and education components will be most effective.