The co-use of alcohol and cannabis is rising in prevalence, yet the mechanisms driving individuals to co-use are not well understood. Subjective response to alcohol or cannabis may predict the desire to use either substance. However, which specific facets of subjective response predict cross-substance craving remains unclear. The present study investigated whether acute administration of alcohol or cannabis facilitates cue-induced craving for the other substance, with an emphasis on the underlying subjective response mechanisms contributing to co-use. This is a secondary analysis of a behavioral pharmacology study that combined alcohol/cannabis administration with a cross-substance cue-reactivity paradigm in individuals who were heavy alcohol and heavy cannabis co-users. Over two sessions, twenty-nine individuals (17 M/12F) self-administered alcohol or cannabis (in a crossover design), and then completed a cue-reactivity exercise with the other substance. Analyses tested how changes in subjective response variables following substance administration predicted cross-substance cue-induced craving. Following alcohol administration, greater subjective ratings of positive mood predicted significantly greater cue-induced cannabis craving (β = 1.14, SE = 0.41, t = 2.80, p = 0.010). Following cannabis administration, lower subjective effects ratings of positive mood/arousal predicted significantly greater cue-induced alcohol craving (β = −1.08, SE = 0.38, t = −2.85, p = 0.009; β = −2.38, SE = 1.13, t = −2.10, p = 0.047). This study identified subject response mechanisms contributing to cross-substance cue induced craving. These mechanisms include increases in positive mood following alcohol use and decreases in positive mood and arousal, akin to increases in relaxation, following cannabis use.