Cabotegravir is a novel therapeutic option for HIV prevention. Similar to the opioid morphine, cabotegravir, undergoes glucuronidation through the enzymes uridine diphosphate glucuronosyltransferase (UGT) in the liver. We hypothesize that their combination could lead to drug-drug interactions, and this notion was explored in both male and female mice. Our findings indicate a better analgesic response to morphine in females compared to male animals, which was to be mediated by μ-opioid receptors and proteins associated with synaptic plasticity. Co-administration with cabotegravir appears to intensify morphine concentrations in the brain and the analgesic response in male animals only. Moreover, cabotegravir-induced fluctuations in the expression of the UGT enzymes correlated with alterations in drug metabolism and excretion and in the production of inflammatory cytokines primarily driven by morphine in the brains and cabotegravir in the liver. The increased levels of inflammatory cytokines in males aligned with noticeable morphological changes in the liver. In summary, co-exposure with cabotegravir changed the biodistribution in the brain, affected liver metabolism, and altered kidney excretion, leading to changes in gene expression and inflammatory effects that could disrupt morphine analgesia responses.