The concept of homeostasis is a central principle in many biological systems, and aims at maintaining systems in a functional state. In the brain homeostatic synaptic plasticity is a well-known mechanism to maintain neuronal networks in a functional homeostasis. Despite there has been a lot of research and characterization of this form of plasticity in animal models, it remains unknown, whether it is also expressed in the human brain. In this study, we investigated the impact of treatment with antiepileptic drugs on neurotransmission and functional properties of layer 2/3 pyramidal cells in the human cortex. Using whole-cell patch-clamp recordings, transcriptome analysis, and confocal imaging, we show that an attenuation of network activity by antiepileptic drugs such as Lamotrigin induces a compensatory strengthening of excitatory neurotransmission in the murine and human neocortex. This was accompanied by changes on a transcriptomic and structural level. Our findings implicate the first evidence of plasticity upon activity deprivation in the adult human cortex induced by the clinical application of antiepileptic drugs. They also provide a possible mechanistic explanation for seizure recurrence after drug withdrawal of antiepileptic treatment. Supported by Deutsche Forschungsgemeinschaft (DFG; CRC/TRR 167).