Abstract The relationship between sleep deprivation, obesity, and systemic inflammation is a critical area of investigation due to its significant impact on health. While it is established that poor sleep adversely affects obesity and metabolic syndromes, the specific mechanisms, particularly subclinical inflammation independent of obesity, remain unclear. This study investigates how sleep quality influences monocyte subclass distribution and its association with systemic inflammation across a spectrum of body mass index categories. In our cohort study, 237 healthy participants were categorized by body mass index. Participants' dietary intake, physical activity, and sleep patterns were objectively tracked through wearable ActiGraph GT3X accelerometer. The data showed that obese individuals had significantly lower sleep quality and higher chronic low-grade inflammation. Nonclassical monocytes increased significantly in obesity, correlating with reduced sleep quality and elevated proinflammatory cytokines. Although body mass index emerged as a significant factor in driving inflammation, mediation analyses further defined that sleep disruption independently contributes to inflammation, regardless of obesity status. Controlled sleep deprivation experiments confirmed these findings, demonstrating reversible increases in nonclassical monocytes expression. This study highlights the importance of sleep quality in regulating immune responses and inflammation in obesity, suggesting that improving sleep quality could reduce inflammation and improve health outcomes.