Objective Identifying the effects of comorbidity on healthcare utilization is critical for understanding the benefits of improved comorbidity management. Asthma is a common respiratory condition, associated with gastrointestinal, metabolic, psychiatric, and other respiratory conditions. Adults with asthma represent a key population in understanding comorbidity and its consequences. The objective was to explore the relationship between comorbidity and overnight hospitalizations in U.S. adults with asthma. Study design and methods A cross-sectional sample of 3,887 subjects aged 20–79 was aggregated from seven cycles (2005–2018) of the National Health and Nutrition Examination Survey (NHANES). The survey design was created using the full seven cycles, then a subpopulation was used for the analysis. Design-based modified Poisson regression with robust standard errors compared the prevalence of overnight hospitalizations in subjects with and without comorbidities. Comorbidity was defined as the presence of one or more additional chronic conditions. Results Over half (61.6%) of patients with asthma reported having comorbidities. The overnight hospitalization prevalence was higher in those with comorbidities (21.6%) than those without (7.4%). The adjusted prevalence ratio of overnight hospitalizations in those with comorbidities vs. those without was 2.02 (95% CI: 1.54–2.66). Conclusions from sensitivity analyses remained the same. Conclusions Comorbidity in U.S. adult asthma patients is associated with increased overnight hospitalizations. Study results concur with examinations of other healthcare utilization outcomes, revealing how comorbidity influences healthcare utilization patterns in patients with asthma. The reduction of overnight hospitalizations should be a targeted goal when developing and evaluating interventions to manage comorbidities in patients with asthma.