A deeper understanding of the molecular processes involved in psychological wellbeing in older adults is essential for advancing knowledge of underlying biological mechanisms. Leveraging proteomics data from 3,262 older adults (mean age=63.5 years, 55% female) of the English Longitudinal Study of Ageing (ELSA), we investigated the cross-sectional and longitudinal associations (before and after protein measurement) between 276 proteins and eudaimonic wellbeing, hedonic wellbeing, life satisfaction, and depressive symptoms, over 20-year span. For positive wellbeing, two proteins (DEFB4A and ECE1) were longitudinally associated with subsequent eudaimonic wellbeing trajectory. We further identified higher concentrations of 7, 8, and 2 proteins were linked to subsequent lower eudaimonic wellbeing, hedonic wellbeing, and life satisfaction, respectively. Sex differences in XCL1 and SLAMF7 were observed, associated with lower eudaimonic and hedonic wellbeing in males. These findings link human psychological wellbeing to regulation of several biological pathways, particularly involving cytokine regulation, neurotrophic signaling, inflammatory and immune systems.