The aim of the present study was to examine the hypothesis that miR-33-5p attenuates morphine state-dependent (StD) memory via the µ opioid receptor by regulating cyclic AMP response element-binding protein (CREB). The effects of post-training morphine and morphine StD memory and their interaction with pre-test naloxone were evaluated using a single-trial inhibitory avoidance paradigm. Then, the hippocampal miR-33-5p gene and pCREB/CREB protein expression profiles were evaluated using quantitative real-time PCR and western blotting, respectively. We found that while post-training morphine and morphine StD memory respectively up- and down-regulate the miR-33-5p expression profile in the hippocampus, the reverse results are true for the expression of pCREB/CREB. Pre-test naloxone antagonized the response. Overall, our findings suggest that the expression levels of miR-33-5p in the hippocampus set the basis for morphine StD memory with low miR-33-5p enabling state dependency. The mechanism is mediated via miR33-5p and CREB signaling with the interaction of the µ opioid receptor. This finding may be used as a potential strategy for ameliorating morphine-induced memory-related disorders.