A retrospective study included 262 patients with acute-on-chronic liver failure (ACLF) who were treated with an artificial liver support system (ALSS). Of these, 56 patients (21.4%) had bleeding episodes during hospitalization. Baseline platelet levels in bleeding patients were significantly lower (59.0 (39.0–89.3) × 10⁹/L) versus nonbleeding patients (88.5 (57.0–121.0) × 10⁹/L; p < 0.001). Low baseline platelet levels were negatively associated with bleeding risk (adjusted OR 0.986; 95% CI 0.976–0.996; p = 0.006). Decline rate and final platelet levels were not significantly associated with bleeding (all p > 0.05). The risk of bleeding was higher in patients with lower initial platelet grades: grade 1 (OR 3.21; 95% CI 1.20–8.59; p = 0.002), grade 2 (OR 7.20; 95% CI 1.4–3.2; p = 0.001) and a combination of grades 2+3 (OR 8.43; 95% CI 2.96–23.99; p < 0.001). The number of ALSS sessions did not affect the rate of platelet decline (p > 0.05).