Reports of escalated discrimination among Asian Americans and Pacific Islanders (AAPIs) due to COVID-19 are alarming, making this a public health priority. However, there are limited empirical studies on the scope and impact of COVID-19-related discrimination among AAPIs. Using the COVID-19 Effects on the Mental and Physical Health of AAPI Survey Study (COMPASS) data (N = 4971; survey period: October 2020–February 2021), which is a U.S.-wide multi-lingual survey, we examined the prevalence of, and factors associated with discrimination experiences attributable to being an AAPI during the COVID-19 pandemic. Overall, 60.7% reported experiencing discrimination; the group prevalence ranged from 80.0% (Hmong) to 40.5% (Native Hawaiians and Pacific Islanders). Multivariable logistic regression models revealed that COVID-19-related factors were associated with many discrimination experiences: having a shelter-in-place order of ≥1 month, living in areas with perceived similar/higher COVID-19 severity, and negative impact in family income/employment due to COVID-19. Additionally, being Asian American (versus Native Hawaiians and Pacific Islanders), females, non-heterosexuals, younger, more severe effect on family income, living in the non-West, and poorer health were significantly correlated with discrimination experiences. Findings may assist in formulating anti-AAPI-discrimination policies and programs at the local, state, and federal levels. Culturally appropriate programs and policies to combat this are urgently needed.