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Memory destabilization is a critical phase in memory reconsolidation, during which the transient disruption of consolidated memory traces allows for the incorporation of new information, supporting memory updating and adaptive behavioral modification. While neurotransmitter release and receptor signaling during memory reactivation are known to trigger memory destabilization, the underlying regulatory networks and dynamic interactions remain unclear. Existing studies often examine neurotransmitters in isolation, lacking a unified framework. This review introduces a novel integrative framework that organizes existing evidence on neurotransmitter-mediated memory destabilization around novelty and prediction error (PE) signaling. By synthesizing experimental findings across dopamine (DA), norepinephrine (NE), acetylcholine (ACh), the glutamatergic/GABAergic systems, and the endocannabinoid system, we analyze how PE and novelty engage distinct yet interacting neural pathways. Integrating experimental data and theoretical concepts from multiple systems, we propose the PE-Novelty-Neurotransmitter Network-a unified framework explaining how multimodal neurotransmitter co-release across the midbrain-locus coeruleus-cortex circuit dynamically regulates the balance between memory stability and flexibility. This review addresses diverse memory types, with a focus on maladaptive memories, while also discussing emotional and nonemotional memories. It further discusses potential clinical implications, particularly how neuromodulatory process related to PE and novelty may inform strategies for modifying maladaptive memories and enhancing cognitive flexibility. By bridging mechanistic insights with translational considerations, this work establishes a unified framework for understanding memory plasticity and informs future efforts to translate basic neuroscience into therapeutic contexts.