Silymarin, a flavonolignan-rich extract of Silybum marianum, is widely recognized for its hepatoprotective potential. While rodent studies predominate, pigs (Sus scrofa) offer a more translationally relevant model due to their hepatic architecture, bile acid composition, and transporter expression, which closely resemble those of humans. This narrative review synthesises current evidence on the chemistry, pharmacokinetics, biodistribution, and hepatoprotective activity of silymarin in porcine models. Available studies demonstrate that when adequate intrahepatic exposure is achieved, particularly through optimised formulations, silymarin can attenuate oxidative stress, suppress inflammatory signalling, stabilise mitochondria, and modulate fibrogenic pathways. Protective effects have been reported across diverse porcine injury paradigms, including toxin-induced necrosis, ethanol- and diet-associated steatosis, metabolic dysfunction, ischemia–reperfusion injury, and partial hepatectomy. However, the evidence base remains limited, with few long-term studies addressing fibrosis or regeneration, and methodological heterogeneity complicates the comparison of data across studies. Current knowledge gaps in silymarin research include inconsistent chemotype characterization among plant sources, limited reporting of unbound pharmacokinetic parameters, and variability in histological scoring criteria across studies, which collectively hinder cross-study comparability and mechanistic interpretation. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. Advances in analytical chemistry, transporter biology, and formulation design are beginning to refine the interpretation of exposure–response relationships. In parallel, emerging computational approaches, including machine-learning-assisted chemotype fingerprinting, automated histology scoring, and Bayesian exposure modeling, are being explored as supportive tools to enhance reproducibility and translational relevance; however, these frameworks remain exploratory and require empirical validation, particularly in modeling enterohepatic recirculation. Collectively, current porcine evidence supports silymarin as a context-dependent yet credible hepatoprotective agent, highlighting priorities for future research to better define its therapeutic potential in clinical nutrition and veterinary practice.