Exposing the adolescent brain to drugs of abuse is associated with increased risk for adult onset psychopathologies. Cannabis use peaks during adolescence, with largely unknown effects on the developing brain. Cannabis' major psychoactive component, Δ-tetrahydrocannabinol (THC) alters neuronal, astrocytic, and microglial signaling. Therefore, multiple cellular and signaling pathways are affected with a single dose of THC. The endogenous cannabinoids (eCBs), N-arachidonoyl ethanolamine (AEA) and 2-arachidonoyl glycerol (2-AG) are members of an interconnected lipidome that includes an emerging class of AEA structural analogs, the lipoamines, additional 2-acyl glycerols, free fatty acids, and prostaglandins (PGs). Lipids in this lipidome share many biosynthetic and metabolic pathways, yet have diverse signaling properties. Here, we show that acute THC drives age-dependent changes in this lipidome across 8 regions of the female mouse brain. Interestingly, most changes are observed in the adult, with eCBs and related lipids predominately decreasing. Analysis of THC and metabolites reveals an unequal distribution across these brain areas; however, the highest levels of THC were measured in the hippocampus (HIPP) in all age groups. Transcriptomic analysis of the HIPP after acute THC showed that like the lipidome, the adult transcriptome demonstrated significantly more changes than the adolescent. Importantly, the regulation of 31 genes overlapped between the adolescent and the adult, suggesting a conserved transcriptomic response in the HIPP to THC exposure independent of age. Taken together these data illustrate that the first exposure to a single dose of THC has profound effects on signaling in the CNS.