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Background: Dry eye disease (DED) is a condition that affects the ocular surface and affects millions of people around the world. In recent years a stepped scheme has been proposed for the treatment of DED, with the use of an artificial tear being the mainstay of treatment. In this scheme, the use of secretagogues is suggested as part of the treatment for patients with moderate to severe affectation. With this systematic review we aim to evaluate the effectiveness and safety of secretagogues for DED.Methods: Electronic databases will be searched; we will include randomized controlled trials that compare secretagogues and artificial tears. Study inclusion will not be restricted on the basis of language or publication status. We will use Google Translate to assess studies written in languages other than English and Spanish. Identification, evaluation, data extraction and assessment of risk of bias will be conducted by two authors of the review, a third review author will resolve any disagreement. The outcomes will be the ocular surface disease index score, osmolarity and tear film break-up time. We will use the Cochrane Collaboration Risk of Bias (RoB) tool for assessing the risk of bias of the included studies. Based on the heterogeneity of the included studies, we will combine the findings in a meta-analysis using a random versus a fixed effect model. If we deem meta-analysis as inappropriate, we will document the reasons and report findings from the individual studies narratively.Discussion: Based on the evidence obtained we will evaluate the effect of Pilocarpine, Cevimeline and Diquafosol and compare it to artificial tears on multiple outcome measures.This systematic review aims to determine the efficacy and safety of the secretagogues pilocarpine, cevimeline and diquafosol to help clinicians in the decision-making process.Registration: PROSPERO CRD42020218407