Estrogen receptors (ERs) and their ligands play a crucial role in physiological and pathophysiological processes, particularly in the central nervous and cardiovascular systems. There is increasing evidence that besides the two cytosolic and nuclear ERs, namely, ERα and ERβ, the seven-transmembrane G protein-coupled ER 1 (GPER1) is of great importance in the molecular mechanisms underlying various neurological and cardiovascular diseases and is probably responsible for sex-specific differences. In contrast to ERα and ERβ, GPER1 mediates its effects through not only transcriptional regulation but also rapid nongenomic signaling. This emphasizes the role of GPER1 in the modulation of acute pathophysiological mechanisms involving changes in diverse signaling pathways related to neurological and cardiological aspects. In this review, we have summarized the role of GPER1 in disorders of excitable tissues, including neuroinflammation, learning and memory, Alzheimer’s disease, Parkinson’s disease, depression and mood disorders, schizophrenia, epilepsy, autism spectrum disorders and attention-deficit/hyperactivity disorder, migraine and pain, cardiovascular hypertension, cardiovascular function and fibrosis, hypertrophy, and atrial fibrillation, with a special focus on its involvement in sex-specific differences. We have assessed reports investigating the role of GPER1 in rodents and humans using in vivo and in vitro data. We have also reviewed the role of nutraceuticals, especially phytoestrogens, in this context. Furthermore, we have discussed the potential of GPER1 as a target for novel therapeutic interventions and prognostic indicator of neurological and cardiovascular diseases with a focus on sex-specific differences.