A child temperament characterized by shyness and avoidance of social interactions is associated with poor peer relationships and emotional problems, yet its long-term associations with adult cardiometabolic health are largely unknown. To examine whether a childhood temperament characterized by shyness and avoidance of social interactions is associated with poor cardiometabolic health. This cohort study included participants who were recruited at birth between April 1991 to December 1992 as part of a prospective longitudinal cohort, the Avon Longitudinal Study of Parents and Children. Follow-up assessments of health behaviors and cardiometabolic health extended into young adulthood (age 24 years). Data analysis was conducted between April and October 2021. Parent reports of temperament across ages 3 to 6 years were used to derive childhood temperament profiles in a longitudinal clustering analysis. Accelerometry measures of adolescent moderate to vigorous physical activity (MVPA) from ages 11 to 15 years and adult social occupation class were examined as mediators using path analyses. At age 24 years, 9 cardiometabolic outcomes were measured through anthropometrics and fasting blood samples: triglyceride levels, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol levels, glycated hemoglobin levels, insulin levels, systolic and diastolic blood pressure, body mass index, and C-reactive protein (CRP) levels. Of the 9491 participants included in the analyses, 4908 (51.7%) were male, and 8668 of 9027 (96.0%) were White. Four childhood temperament profiles were identified: (1) introverted (2810 [29.6%]), (2) extraverted (2527 [26.6%]), (3) conflicted-shy (2335 [24.6%]), and (4) avoidant-shy (1819 [19.2%]). Lower childhood socioeconomic status was a precursor associated with the development of an avoidant-shy temperament (eg, introvert vs avoidant-shy: odds ratio, 1.13; 95% CI, 1.04-1.23). Path analyses showed that avoidant-shy children spent less time in MVPA in adolescence compared with all other temperament profiles (eg, introvert vs avoidant-shy: β = 0.10; b = 0.25; 95% CI, 0.14-0.35; P < .001), which in turn was associated with a cluster of cardiometabolic indices at age 24 years, including lower HDL cholesterol levels (β = 0.07; b = 0.95; 95% CI, 0.12-1.78; P = .03) and higher LDL cholesterol levels (β = −0.07; b = −1.69; 95% CI = −3.32 to −0.06; P = .04), insulin levels (β = −0.10; b = −0.57; 95% CI, −1.04 to −0.10; P = .02), diastolic blood pressure (β = −0.09; b = −0.59; 95% CI, −0.97 to −0.21; P = .002), and body mass index (β = −0.07; b = −0.32; 95% CI, −0.56 to −0.07; P = .01). Additionally, children classified as avoidant-shy attained lower social occupation classes at age 24 years, which was concurrently associated with higher BMI (β = 0.06; b = 0.21; 95% CI, 0.08-0.35; P = .002). Notably, these results were adjusted for a range of early developmental precursors and confounders, suggesting an independent association of temperament. In this cohort study, less engagement in physical activity across adolescence seemed to be a developmental mechanism connecting an avoidant-shy childhood temperament and greater cardiometabolic risks over the life course. Future studies should examine the efficacy of physical activity and social skill programs that specially target the needs of different children to thereby reduce cardiometabolic risks.