Transfusion-related reactions cause unwanted interruptions in blood-product administration and potential complications for patients. The most common reactions are febrile nonhemolytic transfusion reactions (FNHTRs) and allergic transfusion reactions (ATRs). The presence of leukocytes in blood products has been associated with these reactions, and efficacy of leukoreduction in minimizing FNHTRs and ATRs has recently been investigated. In addition, premedication with acetaminophen and diphenhydramine is the most widely used practice in minimizing FNHTRs and ATRs, yet the benefit of this is not supported by research. The aim of this systematic literature review was to evaluate the potential benefits of both of these interventions in minimizing FNHTRs and ATRs and provide recommendations for practice. We found moderate quality evidence with strong recommendations for the practice of leukoreduction in minimizing FNHTRs but not ATRs. We did not find evidence to support the use of premedications in minimizing transfusion-related reactions, and we question the need for this practice in settings where leukoreduction is used.