Antidepressants such as the selective serotonin reuptake inhibitors (SSRIs) have complex temporal effects. They may worsen symptoms during early treatment, they may reduce depressive symptoms over several weeks of treatment, and they may lose effectiveness over more prolonged treatment or after repeated treatment trials. Conceptually, these effects fall within the domain of hormesis, which refers to a biphasic or multiphasic response to a drug or toxin. Hormetic effects are commonly triggered when a drug interacts with homeostatic mechanisms. We develop and evaluate a theoretical framework for understanding how adaptations to SSRIs that restore synaptic homeostasis may partially contribute to their hormetic effects. Specifically, the serotonin system adapts to SSRIs by suppressing the firing of serotonergic neurons, inhibiting the synthesis of serotonin, and reducing the overall content of serotonin in the brain. Moreover, rodent models such as inescapable shock show that serotonin neurotransmission to specific forebrain regions is a necessary, but insufficient cause of depressive symptoms. Our review suggests: (1) early worsening of symptoms may be related to the direct effects of SSRIs on synaptic serotonin; (2) the symptom-reducing effects could be related to the loss of serotonin content in the brain during SSRI exposure; (3) the loss of efficacy over prolonged exposure could be related to the central nervous system equilibrating to the SSRIs. The serotonin system’s adaptations to SSRIs may play a clinically meaningful role in their hormetic effects on depressive symptoms. A complete understanding of SSRIs’ hormetic effects will require exploring temporal dynamics in other neurotransmitter systems.