Background: Childhood cancer survivors (CCS) are often impacted by cancer-related cognitive impairment (CRCI), requiring long-term follow-up care. It is unknown whether survivors reporting CRCI are at higher likelihood to suffer from adverse lifestyle behaviors such as smoking and vaping. Using the Project Forward cohort, we analyzed the prevalence of CRCI and its association with substance abuse. Methods: The Project Forward study surveyed adolescent and young adult CCS between 2015 to 2018 to evaluate the quality of cancer follow-up care. Associations between self-reported CRCI and adverse lifestyle behaviors were examined in multivariable logistic regressions, adjusting for covariates: cancer type, treatment intensity, race/ethnicity, gender, and age at diagnosis. Stratified analysis by recency of latest cancer follow-up care was performed to examine its impact on the risk of substance abuse among CRCI patients. Results: The cohort comprised 1,106 CCS, with median ages of 25.5 years (IQR: 22, 29) at survey completion and 13 years (IQR: 7, 16) at diagnosis, with over half (n = 570, 51.5%) were being Hispanic. A total of 144 (13%) patients self-reported CRCI, with the highest prevalence observed among brain cancer (25.4%) and leukemia (13.3%) survivors. Cancer-related follow-ups were more frequently observed among survivors reporting CRCI, comparing to non-CRCI survivors (66.7% vs 56.9%, p = 0.030). After adjusting for confounders, survivors reporting CRCI were at higher odds to vape with e-cigarettes than those without CRCI (OR = 2.24, 95% CI = 1.24–4.09, p = 0.008). Among those who did not engage any recent cancer follow-up care (n = 455), CRCI was associated with 2.9 times the odds of vaping with e-cigarettes (OR = 2.9, 95% CI = 1.07–7.88, p = 0.037). No association was observed between CRCI and the use of cigarettes, alcohol, or marijuana. Conclusions: Vaping is more prevalent among CCS reporting CRCI, especially those who are less likely to attend follow-up care. Our data suggests the importance of encouraging long-term follow-ups to monitor adverse lifestyle behaviors in CCS experiencing cognitive symptoms and provide timely interventions.