Perfluorooctanesulfonic acid (PFOS) is a ubiquitous perfluoroalkyl substance (PFAS) linked to liver disease and obesity in humans. Binding studies suggest that albumin is a crucial blood protein influencing PFOS toxicokinetics and hepatotoxicity; however, its role has not been mechanistically tested in vivo. This study used an albumin-deficient mouse model to investigate the relevance of albumin in PFOS tissue distribution and liver disease end points. Adult male C57BL/6J wild-type (Alb) and albumin-deficient (Alb) mice were orally gavaged daily for 7 days with either vehicle or PFOS at 0.5 or 10 mg/kg body weight. The measured PFOS concentrations in plasma were significantly lower in Alb mice compared to those in Alb mice, while liver concentrations were significantly higher in Alb mice. Binding experiments confirmed these findings, indicating that PFOS toxicokinetics are driven by plasma and tissue binding. Significant changes in liver protein expression did not translate into differences in liver disease end points between genotypes, suggesting the need for chronic exposure studies. Our data imply that disease-related albumin deficiency in humans can influence PFAS toxicokinetics and susceptibility to hepatotoxicity. Our framework using knockout mice can be adapted in future studies to assess the relevance of protein binding and membrane transporters in PFAS distribution and elimination.