Zinc is a trace element that plays an important role in the immune system and cell growth. The role of zinc in cancer treatment has been discussed for some time, however without reaching an evidenced-based consensus. Therefore, we aim to critically examine and review existing evidence on the role of zinc during cancer treatment. In January 2019, a systematic search was conducted searching five electronic databases (Embase, Cochrane, PsychINFO, CINAHL and PubMed) to find studies concerning the use, effectiveness and potential harm of zinc therapy on cancer patients. Out of initial 5244 search results, 19 publications concerning 23 studies with 1230 patients were included in this systematic review. The patients treated with zinc were mainly diagnosed with head and neck cancer and underwent chemo-, radio- or concurrent radio-chemotherapy. Interventions included the intake of different amounts of zinc supplements and oral zinc rinses. Outcomes (primary endpoints) investigated were mucositis, xerostomia, dysgeusia, pain, weight, dermatitis and oral intake of nutrients. Secondary endpoints were survival data, quality of life assessments and aspects of fatigue, immune responses and toxicities of zinc. The studies were of moderate quality reporting heterogeneous results. Studies have shown a positive impact on the mucositis after radiotherapy. No protection was seen against mucositis after chemotherapy. There was a trend to reduced loss of taste, less dry mouth and oral pain after zinc substitution. No impact was seen on weight, QoL measurements, fatigue, and survival. The risk of side effects from zinc appears to be relatively small. Zinc could be useful in the prevention of oral toxicities during irradiation. It does not help in chemotherapy-induced side effects.