Sexual and gender minority (SGM) college students experience compounding psychological effects as a result of the COVID-19 pandemic. Using latent profile analysis of cross-sectional data from a sample of SGM students (n = 565) we tested for a syndemic of victimization, internalized LGBTQ + stigma, racism, racialized heterosexism/cisgenderism, family rejection, and isolation associated with psychological distress. We also tested if increases in these factors since the start of the COVID-19 pandemic were associated with greater psychological distress among syndemic profiles. We identified four profiles: 'Lowest syndemic factors' (reference), 'High isolation only', 'High isolation and rejection only', and 'High syndemic'. The greatest distress was observed among the 'High syndemic' profile (aPR = 2.99, 95% CI 2.20, 4.06), followed by the 'High isolation and rejection only' profile (aPR = 2.11, 95% CI 1.61, 2.76), and the 'High isolation only' profile (aPR = 1.32, 95% CI 1.03, 1.70). Among the 'High syndemic profile', increases in every factor since the start of the COVID-19 pandemic were associated with greater psychological distress. The strongest associations were seen among increased victimization (aPR = 5.85, 95% CI 1.33, 25.71). Victimization, internalized LGBTQ + stigma, racism, family rejection, and isolation form a syndemic among SGM students, which has magnified since the start of the COVID-19 pandemic.