Abstract Objective Systemic inflammation, such as interleukin-6 (IL-6) and C-reactive protein (CRP), can affect an individual’s functioning and is a consequence of stress-related physiological changes, especially as one ages. Cognitive functioning is a critical factor of healthy aging and strongly associated with sleep and chronic conditions/symptoms. IL-6 can induce CRP production, leading to downstream effects, however IL-6 levels may also contextualize how CRP may be linked to cognition. Methods Using MIDUS waves 2 (M2) and 3 (M3) data, the participants included 770 adults (58.1% Female; 84.9% white; 53.28 ± 10.7 years) who completed two BTACT cognitive assessments over a ten-year period and provided blood samples and psychosocial self-report data at M2. Using PROCESS macro (model 1), we examined the interaction of proinflammatory markers on cognitive decline. Results M2 IL-6 interacted with M2 CRP to predict M3 cognition while accounting for age, education, race, gender, sleep, and M2 cognition (ΔR2 = 0.002, F(1,759) = 4.74, p = 0.030). Specifically, among those with lower IL-6, their CRP levels were negatively linked to M3 cognitive performance (b = −0.114, p = 0.007), while for those with higher IL-6, there was no relationship (b = −0.008, p = 0.842). Conclusion Findings suggest that a dynamic relationship exists between inflammatory markers and cognitive function. Not only can IL-6 directly affect CRP, it may also provide additional context on how a clinically relevant inflammatory marker may be related to cognitive decline. From a stress and adaptive systems lens, further research should investigate how IL-6 may highlight the accumulation of stressful life events or other chronic psychosocial factors, using a more holistic approach to cognitive aging.