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We evaluated how much cardiorespiratory fitness (CRF)-related genetics contribute to the risk of common noncommunicable diseases (NCDs) and mortality, and whether individuals with different levels of CRF and genetic predispositions differ in health characteristics. We used a validated SBayesR-based genome-wide polygenic score, leveraging information from 905 707 single-nucleotide polymorphisms, to measure CRF genetics (PGS CRF). Associations with register-based incident NCDs and mortality were analyzed using Cox proportional hazards models in the FinnGen cohort (N = 262 137; 53.5-years at baseline, 52.0% women) and replicated in the HUNT3 cohort (N = 26 115; 59.0-years, 52.4% women). In HUNT3, we also compared the health characteristics of individuals having age- and sex-specific high or low CRF (V̇O_2peak), and high or low PGS CRF (N = 1316). PGS CRF was negatively associated with any CVD (hazard ratio [HR] 0.99, 95% confidence interval 0.98-1.00), ischemic heart diseases (HR 0.98, 0.97-0.99), hypertensive diseases (HR 0.99, 0.97-1.00), stroke (HR 0.98, 0.97-1.00), lung cancer (HR 0.95, 0.92-0.97), chronic lower respiratory disease (HR 0.98, 0.97-0.99), chronic obstructive pulmonary disease (HR 0.97, 0.95-0.99), type 2 diabetes (T2D) (HR 0.96, 0.95-0.97), and all-cause mortality (HR 0.98, 0.97-0.99), per each standard deviation increase in PGS. Replication analyses supported the association with T2D. No differences in health characteristics were observed by genetic predisposition to CRF, while those with high V̇O_2peak had a healthier profile in comparison to those with low V̇O_2peak. The genome-wide PGS explains only a fraction of the CRF phenotype, yet some small associations were observed, particularly for T2D incidence.