Objective: The prevalence of obesity increases with age and is higher in each younger generation (unfavorable generation shift). This may influence patterns of oxidative stress and inflammation. Age-related changes and generation shifts in markers of oxidative stress and inflammation were investigated, specifically addressing the role of body mass index (BMI). Methods: Four generations (aged 26–35, 36–45, 46–55, and 56–65 at baseline) (N = 5,155) were examined every 5 years for 15 years between 1993 and 2012. Random coefficient analyses were used to study age-related changes and generation shifts in BMI, γ-glutamyltransferase (GGT), uric acid (UA), and C-reactive protein (CRP). Results: Levels of BMI, UA, and CRP increased in all generations up to age 75, whereas GGT increased up to age 55. No consistent generation shifts were observed for GGT, UA, and CRP (P ≥ 0.05). Participants with a stable BMI (change ≤1 kg/m2/15 years) had either no or small increases with age in GGT, UA, and CRP, whereas participants with increasing BMI (increase >1 kg/m2/15 years) had much larger increases (P < 0.01). Conclusions: The unfavorable age-related changes in obesity-related biochemical markers, particularly among individuals with increasing BMI, show the importance of maintaining a healthy weight to improve population levels of oxidative stress and inflammation.