Background: The COVID-19 pandemic continues to have a disproportionate effect on ethnic minorities. Across countries, greater vaccine hesitancy has been observed among ethnic minorities. After excluding foreign domestic helpers, South Asians make up the largest proportion of ethnic minorities in Hong Kong. It is necessary to plan for COVID-19 vaccination promotional strategies that cater to the unique needs of South Asians in Hong Kong., Objective: This study investigated the prevalence of COVID-19 vaccine uptake among a sample of South Asians in Hong Kong. We examined the effects of sociodemographic data and factors at individual level (perceptions), interpersonal level (information exposure on social media), and sociostructural level (cultural) based on the socioecological model., Methods: A cross-sectional web-based survey was conducted on May 1-31, 2021. Participants were South Asian people aged 18 years or older living in Hong Kong; able to comprehend English, Hindi, Nepali, or Urdu; and having access to a smartphone. Three community-based organizations providing services to South Asians in Hong Kong facilitated the data collection. The staff of the community-based organizations posted the study information in WhatsApp groups involving South Asian clients and invited them to participate in a web-based survey. Logistic regression models were fit for data analysis., Results: Among 245 participants, 81 (33.1%) had taken at least one dose of the COVID-19 vaccine (one dose, 62/245, 25.2%; and both doses, 19/245, 7.9%). After adjusting for significant background characteristics, cultural and religious reasons for COVID-19 vaccine hesitancy were associated with lower COVID-19 vaccine uptake (adjusted odds ratio [AOR] 0.83, 95% CI 0.71-0.97; P=.02). At the individual level, having more positive attitudes toward COVID-19 vaccination (AOR 1.31, 95% CI 1.10-1.55; P=.002), perceived support from significant others (AOR 1.29, 95% CI 1.03-1.60; P=.03), and perceived higher behavioral control to receive COVID-19 vaccination (AOR 2.63, 95% CI 1.65-4.19; P<.001) were associated with higher COVID-19 vaccine uptake, while a negative association was found between negative attitudes and the dependent variable (AOR 0.73, 95% CI 0.62-0.85; P<.001). Knowing more peers who had taken the COVID-19 vaccine was also associated with higher uptake (AOR 1.39, 95% CI 1.11-1.74; P=.01). At the interpersonal level, higher exposure to information about deaths and other serious conditions caused by COVID-19 vaccination was associated with lower uptake (AOR 0.54, 95% CI 0.33-0.86; P=.01)., Conclusions: In this study, one-third (81/245) of our participants received at least one dose of the COVID-19 vaccine. Cultural or religious reasons, perceptions, information exposure on social media, and influence of peers were found to be the determinants of COVID-19 vaccine uptake among South Asians. Future programs should engage community groups, champions, and faith leaders, and develop culturally competent interventions., (©Akansha Singh, Angel Hor Yan Lai, Jingxuan Wang, Saba Asim, Paul Shing-Fong Chan, Zixin Wang, Eng Kiong Yeoh. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 09.11.2021.)