Tobacco and cannabis are frequently used together during pregnancy. However, relatively little is known about how co-use and related maternal risk factors impact toddler reactivity. One understudied risk factor is maternal experience of anger/hostility, despite evidence suggesting that individuals who use substances experience more anger/hostility. In addition, mood unpredictability in anger/hostility (MUA), a relatively novel construct, may be particularly important for mothers who use substances as they attempt to cut down or quit during pregnancy and may also impact toddler reactivity. Importantly, prenatal exposures may also impact toddler outcomes via continued postnatal exposure and infant reactivity. We examined a conceptual model linking prenatal tobacco and tobacco-cannabis co-use, maternal anger/hostility, and unpredictability in anger/hostility with toddler reactivity in a sample (N = 247 at recruitment, 190 at toddler age; N = 247 for model testing) of dyads recruited during the first trimester of pregnancy into a tobacco group (use of combustible cigarettes; including sub-group of women who also used cannabis) and a non-substance use group. Results indicated a direct effect of prenatal co-exposure on blunted toddler reactivity for males only. Mothers who used substances prenatally had the highest levels of anger/hostility and MUA. Prenatal anger/hostility and MUA were associated with higher reactivity at infancy which in turn, was associated with higher toddler reactivity. Prenatal co-exposure and higher prenatal maternal anger/hostility was associated with continued postnatal exposure to cannabis which in turn, was associated with higher reactivity at toddlerhood. Results highlight the importance of examining prenatal co-exposure and continued postnatal cannabis exposure as well as associated maternal risk factors such as anger/hostility and MUA for toddler developmental outcomes.