Background and Objective <p>Both obesity and sleep disturbance have been linked to inflammation. However, the role that inflammation plays in the relationship between sleep disturbance and obesity remains unclear.</p> Methods <p>We examined pairwise associations between inflammatory markers (neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) level, sleep disturbance, and obesity in a robust, ethnically diverse sample (n = 34,704) from the National Health and Nutrition Examination Survey (NHANES).</p> Results <p>We found higher levels of inflammatory markers in participants with obesity and/or sleep disturbance compared to those without obesity or sleep disturbance. Sleep disturbance was positively associated with inflammatory markers and obesity even after considering a wide range of potential confounders (e.g., age, sex, race). Inflammatory markers mediated a marginal portion (CRP, 40.203%; <i>P</i> &lt; 0.0001) of the potential effects of sleep disturbance on obesity.</p> Conclusions <p>Our research showed that C-reactive protein level, sleep disturbance, and obesity are pairwise correlated. Increased C-reactive protein level mediates the association between sleep disturbance and obesity.</p>