Thyroid cancer is the most common endocrine malignancy. Most thyroid cancer types respond well to conventional treatment consisting of surgery and radioactive iodine (RAI) therapy. Unfortunately, some thyroid cancer types are resistant to surgical and RAI therapy. Multikinase inhibitors (MKIs) can be used in the treatment of advanced refractory thyroid cancers. The objective of this review is to give an update on MKI treatment (lenvatinib, sorafenib, sunitinib, cabozantinib, pazopanib, vandetanib) of thyroid cancer, regarding its efficacy and safety profile. We evaluated 212 articles through a PubMed search. A total of 20 articles met the inclusion and none the exclusion criteria. The studies showed promising progression-free survival rates compared to placebo treatment from earlier studies and similar or better results compared to the SELECT and DECISION trials. Adverse effects (AEs) are substantial in the treatment with MKIs. Almost all patients treated with these novel drugs experienced AEs. It is therefore crucial to focus on the management of AEs for a decent long-term outcome. The AEs are often more severe in patients with high efficacy of MKIs, which could indicate a correlation. Taken together, the novel therapeutic regimen with MKIs has shown favorable results in otherwise treatment-resistant thyroid cancer.