In this paper, we discuss a unifying hypothesis, supported by Hebbian theory, that postulates that both delirium/toxic-metabolic encephalopathy (DTME) and hospital-acquired weakness (HAW) obey to a similar underlying anatomic site of dysfunction: the synapse. A brief historical and current state of endorsing knowledge summarizing its plausibility is presented. Both DTME and HAW are commonly encountered conditions in clinical practice. It is estimated that up to 30-70% of hospitalized patients will develop DTME and/or HAW. The currently available explanations in the pathophysiology of these conditions vary widely, and there is no consensus explanation on their etiopathogenesis. The disease state itself, inflammation, exo- and endo-toxins and decreased use of the synapse leads to their dysfunction which likely extends to other key cells in the micromilieu such as microglia, astrocytes, capillaries, Schwann cells, oligodendrocytes, and the blood brain barrier, all of which participate in the homeostasis and wellbeing of the synapses. Additional disruption of the micromilieu or presence of synaptotoxins (such as benzodiazepines, cytokines, anesthetics, and others) would allow entry into the neural tissue that could induce, aggravate or accelerate the synaptic dysfunction. As we enter the era of the connectome and synaptome, the Hebbian-endorsed synapse-centered hypothesis (heterogenous neuronal microdisconnections) attempts to unify the hypotheses of delirium/toxic-metabolic encephalopathy and hospital-acquired weakness into a single etiopathomechanism.