Two nonionic POEA surfactants (CAS No. 61791-26-2), TA15 and TH30, were tested to establish their acute pathological effects and lethal concentrations (LC50) in Piaractus brachypomus. Both compounds are nonionic surfactants produced by the alkoxylation of ethylene oxide with tallow amine, and they are used in variety of industries such as textiles, paints, metal working, agriculture, and polish manufacture. Fish were exposed to six concentrations of TA15 (0.2–4.0 mg/L) or TH30 (8–140 mg/L) for 96 h. The LC50 for TA15 was 2.08 mg/L and for TH30 47.32 mg/L. The main clinical signs observed in fish exposed to 4 mg/L of TA15 and 32 to 140 mg/L of TH30, were lethargy, loss of shoaling behavior, respiratory distress, changes in swimming pattern, such as, loss of balance and abnormal buoyancy, prolapse of the lower lip and superior location in the water column. The highest concentrations of these compounds induced nervous signs and collapse. The relevant macroscopic lesions were skin and fins erosions with necrotic lysis of the caudal peduncle. In addition, hemorrhages in mouth, branchial arches, and petechial hemorrhages in skin were observed. An increased fluid in the celomic cavity and meningeal hemorrhages were also evident. Organs as gills, liver, brain, and anterior kidney presented severe lesions at the highest concentrations of each compound. For the first time, it is reported lesions in interrenal tissues and choroidal bodies, as well as severe telencephalic lesions associated with the POEA toxicity. These last lesions were more severe in fish exposed to TA15 than to TH30, although the pattern of injuries was similar with both substances. According to the Global Harmonized System of Classification and Labelling of Chemical (GHS) by the United Nations, we reported that TA15 is classified as Acute Category 2 and TH30 is Acute Category 3 for white cachama. Due to the low LC50 and the highly toxic effects of both POEA compounds for neotropical fish, a revision of the regulation of the use of herbicide mixtures by Colombian legislation is necessary.