Inflammation likely mediates associations between nicotine use and negative health outcomes. Sex differences have been observed in nicotine use–inflammation links, and physiological processes during puberty might allow for these differences to arise. In this cross-sectional study of 498 youth (ages 8–13, 52% girls, 77% with history of child maltreatment (CM) investigation), sex-differentiated associations between self-reported nicotine use and high-sensitivity C-reactive protein (hs-CRP) were explored. Additionally, self-reported pubertal stage was investigated as a moderator of such nicotine use–hs-CRP links. Hierarchical generalized estimating equation models were adjusted for a wide range of adversity effects: CM investigation history derived from state records, self- and caregiver-report of traumatic life events, adversity-related demographic risk factors (i.e., identification with historically marginalized racial and ethnic groups, household income), and other characteristics that may influence the variables of interest (e.g., medication use, age, body mass index). Nicotine use had a negative main effect on hs-CRP among boys (β = -0.50, p = .02), and pubertal stage did not moderate this association (β = 0.06, p = .71). In contrast, pubertal stage moderated the association between nicotine use and hs-CRP among girls (β = 0.48, p = .02) such that a positive association between nicotine use and hs-CRP levels was stronger at more advanced pubertal stages (β = 0.45, SE = 0.21, 95% CI [0.03, 0.87]). Findings suggest that puberty may influence the effect of nicotine on inflammation in sex-differentiated ways and have implications for timing of prevention and treatment efforts geared toward reducing nicotine use and subsequent inflammation-related health risk among youth.