As a multi-systemic disease, COVID-19 infection engendered a rise in co-occurring mental and physical health symptoms, particularly affecting the Latinx population. The current work sought to evaluate the main and interactive influence of acculturative stress and anxiety sensitivity in terms of mental and physical health symptoms among 181 Latinx persons (30.4% female, M_age = 34.1 years, SD = 8.20). Data were collected during a period of high COVID-19 impact (2020-2021) and analyses included five separate, two-step hierarchical regressions that were conducted for each of the criterion variables: (1) fear of coronavirus; (2) somatic symptoms; (3) fatigue severity; (4) anxiety symptoms; and (5) depression symptoms. For all analyses, step 1 covariates included years living in the U.S. COVID-19 impact, gender identity, education, and work life distress and home life distress. Results revealed an interactive effect of anxiety sensitivity and acculturative stress on COVID-19 fear, unique main effects for both anxiety sensitivity and acculturative stress on COVID-19 related fear and somatic symptoms, and main effects for anxiety sensitivity alone in relation to fatigue severity, anxiety, and depression. Overall, this study represents an initial investigation of the associations between acculturative stress, anxiety sensitivity, and a range of salient COVID-19 related outcomes among Latinx persons.