Lenvatinib, a multi-kinase inhibitor, has demonstrated improved outcomes for patients with hepatocellular carcinoma (HCC) in clinical trials. The phase 3 REFLECT trial confirmed the noninferiority of lenvatinib to sorafenib for overall survival of HCC patients and indicated clinical benefits in efficacy over sorafenib. Adverse events (AEs) included hypertension, diarrhea, decreased appetite, decreased weight, fatigue, palmar-plantar erythrodysesthesia, and proteinuria. Areas covered: AEs arising in HCC patients during lenvatinib treatment often lead to treatment interruption, dose reduction, or treatment discontinuation. However, reduced lenvatinib exposure may prevent patients from getting the full potential benefit of lenvatinib therapy. We first review the clinical data on lenvatinib, including efficacy and safety. Next, we review the common AEs associated with lenvatinib therapy and provide guidance on how to optimally prevent, detect, and manage these events while minimizing interruptions in lenvatinib treatment. Expert opinion: By fully understanding the common AEs associated with lenvatinib therapy and the proper management of emerging AEs, clinicians may ensure that HCC patients can fully benefit from the potential clinical efficacy of lenvatinib, with fewer unnecessary safety risks.