Grains are major farm animals’ diet ingredients, and one of the main concerns is when are mycotoxin (MyT) contaminated, compromising animals’ health, performance, and product safety. Among the natural phytocompounds that are being used to prevent MyT damage, silymarin (SIL), an extract from the seed of the milk thistle (MT) is a suitable candidate. This review aims to examine the scientific evidence concerning the anti-MyT toxicity effects of MT/SIL in poultry and livestock. In vitro and in vivo studies (n = 27) showed that MT whole plant, seed, or SIL-standardized extract had positive effects on animal health, performance, and restoring the hepatic activity, with a reduction of organ lesions caused by MyT. Furthermore, showed utility for combating MyT-immunodepression, improving intestinal health, and limiting the excretion of toxins residues in food of animal origin, although in some cases, MT/SIL supplementation does not produce appreciable effects. The use of MT in animal nutrition can be useful since the bioactive compounds, also if present in variable amounts, can help the animals to counteract the effects of MyT. The use of the phytoextract of SIL, due to its cost, can be useful if it reported the specific bioactive compounds, recognize for their pharmacological activities.