The current study aimed to investigate the longer-term impact of everyday discrimination and major lifetime discrimination at Time 1 (T1; 2008 and 2010) on couple relationship functioning at Time 3 (T3; 2016 and 2018) across 8 years. It also aimed to explore if psychological (measured by depressive symptoms) and physiological stress responses (measured by allostatic load) at Time 2 (T2; 2012 and 2014) mediated the longitudinal association between discrimination and couple relationship functioning among middle-aged and older-aged adults in the United States (U.S.). To answer the study aims, I conducted a longitudinal mediation path analysis (N = 2,344) in Mplus Version 8 using data from the Health and Retirement Study, an ongoing national survey of the health and aging experience of U.S. adults aged 51 and older residing in the community. The primary longitudinal mediation model with control variables demonstrated good model fit (χ2[4] = 21.78, p < 0.01, CFI = 0.99, RMSEA = 0.04, SRMR = 0.01). The analysis results suggested that depressive symptoms at T2 significantly mediated the longitudinal association between the two types of discrimination and the two types of couple relationships spanning 8 years while controlling for race, age, gender, education, number of reasons for everyday discrimination and T1 assessments of couple support and couple strain. However, allostatic load was not found to be a significant mediator between the two types of discrimination and the two aspects of couple relationship functioning (couple support and couple strain). The direct relationship between discrimination (everyday and major lifetime discrimination) and couple relationship functioning (couple strain and couple support) was not significant either. The results from the multi-group analysis suggested that several structural paths differed significantly across gender, age groups, and number of reasons for everyday discrimination, but none of the paths differed significantly based on race. Overall, the current study did not find evidence supporting the pathway from perceived discrimination to couple relationship functioning through allostatic load. It provided evidence supporting depressive symptoms as a mediating mechanism between perceived discrimination and couple relationship functioning. Future work should develop innovative methods for assessing and measuring allostatic load to test its possible mediation role between perceived discrimination and couple relationship functioning. Moreover, effective and culturally-responsive interventions and programs are needed to decrease all types of discrimination and depression in order to improve couple relationship functioning among middled-aged and older-aged adults in the U.S.