AbstractIntroductionThis protocol describes a systematic review and meta‐analysis to evaluate the clinical effects of mixing short‐ and long‐acting local anaesthetics in peripheral nerve blocks. Clinicians often combine short‐ and long‐acting local anaesthetics to achieve a briefer onset time. However, this may come with a prize, namely a shorter total duration of the block, which is of clinical importance.ObjectiveThis systematic review aims to strengthen the knowledge of the clinical effects associated with this practice. The primary outcome is the duration of block analgesia. Secondary outcomes are block onset time, sensory and motor block duration. Exploratory outcomes are postoperative pain scores, cumulative 24‐h opioid consumption and the prevalence of serious adverse events.MethodsWe will conduct a meta‐analysis of the extracted data, and the risk of bias for each study will be evaluated. We will perform a Trial Sequential Analysis, subgroup, and sensitivity analyses and assess the overall risk of publication bias. Finally, we will evaluate the review using the GRADE principles.