Midkine (MDK) is a multifunctional secreted protein that can act as a cytokine or growth factor regulating multiple signaling pathways and being implicated in fundamental cellular processes, such as survival, proliferation, and migration. Although its expression in normal adult tissues is barely detectable, MDK serum levels are found to be elevated in several types of cancer, including hepatocellular carcinoma (HCC). In this review, we summarize the findings of recent studies on the role of MDK in HCC diagnosis and progression. Overall, studies show that MDK is a powerful biomarker for HCC early diagnosis, as it can differentiate not only between HCC patients and normal individuals but also between HCC patients and patients with other liver pathologies. It is correlated with high recurrence rates and was shown to be valuable for the diagnosis of early-stage HCC, even in patients negative for α-fetoprotein (AFP), the most commonly used biomarker for HCC diagnosis. A comparison with AFP reveals that MDK is inferior to AFP with regard to specificity but significantly superior with regard to sensitivity, which further indicates the need for using both biomarkers for more effective HCC diagnosis.