Serotonin 5-hydroxytryptamine (5-HT) is a key neurotransmitter for the modulation and/or regulation of numerous physiological processes and psychiatric disorders (e.g., behaviors related to anxiety, pain, aggressiveness, etc.). The periaqueductal gray matter (PAG) is considered an integrating center for active and passive defensive behaviors, and electrical stimulation of this area has been shown to evoke behavioral responses of panic, fight-flight, freezing, among others. The serotonergic activity in PAG is influenced by the activation of other brain areas such as the medial hypothalamus, paraventricular nucleus of the hypothalamus, amygdala, dorsal raphe nucleus, and ventrolateral orbital cortex. In addition, activation of other receptors within PAG (i.e., CB1, Oxytocin, µ-opioid receptor (MOR), and γ-aminobutyric acid (GABA_A)) promotes serotonin release. Therefore, this review aims to document evidence suggesting that the PAG-evoked behavioral responses of anxiety, panic, fear, analgesia, and aggression are influenced by the activation of 5-HT_1A and 5-HT_2A/C receptors and their participation in the treatment of various mental disorders.