Raddi (Anacardiaceae) is popularly known in Brazil as and has pharmacological use as an astringent, antidiarrheal, anti-inflammatory, depurative, diuretic, and antifebrile agent. Although the neuropathic antinociceptive potential of fruits has already been investigated, this study is the first one to analyze the acute antinociceptive effect of the essential oil of (female) leaves (EOFSt) on adult zebrafish. EOFSt was submitted to antioxidant activity evaluation by two methods (ferrous ion-chelating capacity [FIC] and β-carotene). The animals ( = 6/group) were treated orally (20 μL) with EOFSt (0.1, 0.5, or 1.0 mg/mL) or vehicle (0.9% sodium chloride [NaCl]; 20 μL), and submitted to nociception (formalin, cinnamaldehyde, capsaicin, glutamate, acidic saline, and hypertonic saline). Possible neuromodulation mechanisms, as well motor alterations and toxicity were also evaluated. In the FIC assay, EOFSt showed ferrous ion-chelating capacity in ∼40% to 90%. Regarding the β-carotene bleaching assay, EOFSt showed inhibition in a 58% to 80% range. Oral administration of EOFSt showed no acute toxicity and did not alter the locomotor system of aZF, and reduced the nociceptive behavior in all tested models. These effects of EOFSt were significantly similar to those of morphine, used as a positive control. The antinociceptive effect of EOFSt was inhibited by naloxone, L-NAME, ketamine, camphor, ruthenium red, and amiloride. The antinociceptive effect of the EOFSt cornea was inhibited by capsazepine. EOFSt has the pharmacological potential for acute pain treatment and this effect is modulated by the opioid system, NMDA receptors, and transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid 1 (TRPV1), and acid-sensing ion channels. The EOFSt also has the pharmacological potential for corneal pain treatment and this effect is modulated by the TRPV1 channel.