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Abstract In the United States, Asian and Pacific Islander (A/PI) communities have faced significant discrimination and stigma during the COVID-19 pandemic. We assessed the association between discrimination and depression, anxiety, and loneliness symptoms among Asian or Pacific Islander adults (n = 543) using data from a 116-item nationally distributed online survey of adults (≥ 18 years old) in the United States conducted between 5/2021–1/2022. Discrimination was assessed using the 5-item Everyday Discrimination Scale. Anxiety, depression, and loneliness symptoms were assessed using the 2-item Generalized Anxiety Disorder, 2-item Patient Health Questionnaire, and UCLA Loneliness Scale—Short form, respectively. We used multivariable logistic regression to estimate the association between discrimination and mental health. Overall, 42.7% of participants reported experiencing discrimination once a month or more. Compared with no discrimination, experiencing discrimination once a month was associated with increased odds of anxiety (Adjusted Odds Ratio [aOR] = 2.60, 95% CI = 1.38–4.77), depression (aOR = 2.58, 95% CI = 1.46–4.56), and loneliness (aOR = 2.86, 95% CI = 1.75–4.67). Experiencing discrimination once a week or more was associated with even higher odds of anxiety (aOR = 6.90, 95% CI = 3.71–12.83), depression, (aOR = 6.96, 95% CI = 3.80–12.74), and loneliness (aOR = 6.91, 95% CI = 3.38–13.00). Discrimination is detrimental to mental health, even at relatively low frequencies; however, more frequent discrimination was associated with worse mental health symptoms. Public health interventions and programs targeting anti-A/PI hate and reducing A/PI mental health burden are urgently needed.