Chronic morphine exposure affects neuroplasticity in the hippocampus, a key area for learning and memory. Since, novelty exploration influence rodent hippocampal plasticity, the aim of this study was to investigate the effects of habituation to novel contexts and odors on hippocampal plasticity in morphine-tolerant rats. For this purpose, neurogenesis markers, dendritic spine density and mRNA levels for various genes encoding neurotrophic factors were evaluated in the hippocampus tissue (ventral, vH vs. dorsal, dH) of male rats. Habituation to the new environment was established using animal models of morphine tolerance. Following multiple exposures to a novel context (open field habituation, OFH) or a series of novel odors (odor habituation, OH), markers (Ki67 or DCX) associated with neurogenesis were found to be lower in the morphine-tolerant rats that underwent habituation than the non-habituated morphine-tolerant rats, with specific regions (dH, vH), being differently influenced by specific type of habituation (OFH, OH, respectively). Further results showed subregion and habituation specific effects on the number of dendritic spines per spine type or levels of neurotropic factors including BDNF and TrkB mRNA levels in the dH and vH in morphine-tolerant rats that underwent habituation as compared to the non-habituated morphine-tolerant rats. We provide new evidence that habituation to novel contexts and novel odors appears to affect hippocampal plasticity in morphine-tolerant rats and that pro-plasticity molecules appear to mediate habituation effects on morphine tolerance plasticity.