Evidence has shown that indoxyl sulfate (IS) and p-cresyl sulfate (PCS) may be alternative predictors of clinical outcomes in chronic kidney disease (CKD). Both toxins are derived from the gastrointestinal tract and metabolised in the liver. However, it is unclear whether the liver affects the production of IS and PCS. Here, we explore the association between IS and PCS levels in liver cirrhosis and a CKD-based cohort (N = 115). Liver and kidney function was assessed and classified by a Child-Pugh score (child A-C) and a modified version of the Modification of Diet in Renal Disease (MDRD) equation (Stages 1-4), respectively. An animal model was also used to confirm the two toxin levels in a case of liver fibrosis. In patients with early liver cirrhosis (child A), IS and PCS were significantly associated with CKD stages. In contrast, serum IS and PCS did not significantly change in advanced liver cirrhosis (child C). A stepwise multiple linear regression analysis also showed that T-PCS was significantly associated with stages of liver cirrhosis after adjusting for other confounding factors (B = -2.29, p = 0.012). Moreover, the serum and urine levels of T-PCS and T-IS were significantly lower in rats with liver failure than in those without (p<0.01, p<0.05 and p<0.01, p<0.05, respectively). These results indicated that in addition to the kidneys, the liver was an essential and independent organ in determining serum IS and PCS levels. The production rate of IS and PCS was lower in patients with advanced liver cirrhosis.