Psychological stress, defined as a relationship between the person and their socioenvironmental context that is appraised as exhausting the resources of a person, has long been shown to affect concurrent and long-term health outcomes. Previous research has focused on the bidirectional natures of stress with biopsychosocial constructs, including sleep, inflammation, and cognition. However, how these factors may be interrelated has been largely unexplored. Thus, our aim was to investigate via multiple path analyses the direct and indirect effects of stress on sleep, inflammation (C-reactive protein, tumor necrosis factor-alpha, and interleukin-6), and concurrent and longitudinal cognitive functioning in middle-aged US adults. Results indicated that stress was a significant predictor of concurrent sleep quality and inflammation. Cross-sectional analyses indicated that there was some support for a pathway from stress to cognitive functioning via sleep and C-reactive protein; however, longitudinally these findings were not replicated when we controlled for cognition at time 1, potentially indicating that the effects of stress on cognition are consistent over time among middle-aged adults. An exploratory moderated mediation indicated that age and sex may mediate the indirect relationship of stress on cognition via inflammation. Overall, we found that to encourage healthy aging and limit cognitive decline over time, stress and inflammation reduction efforts, along with treatment for sleep issues, may improve outcomes among middle-aged adults.