Background: Existing self-management and behavioural interventions for diabetes vary widely in their content, and their sustained long-term effectiveness is uncertain. Autonomy supporting interventions may be a prerequisite to achieve ‘real life’ patient engagement and more long-term improvement through shared decision-making and collaborative goal setting. Autonomy supportive interventions aim to promote that the person with diabetes’ motivation is autonomous meaning that the person strives for goals they themselves truly believe in and value. This is the goal of self-determination theory and guided self-determination interventions. Self-determination theory has been reviewed but without assessing both benefits and harms and accounting for the risk of random errors using trial sequential analysis. The guided self-determination has not yet been systematically reviewed. The aim of this protocol is to investigate the benefits and harms of self-determination theory-based interventions versus usual care in adults with diabetes. Methods/design: We will conduct the systematic review following The Cochrane Collaboration guidelines. This protocol is reported according to the PRISMA checklist. A comprehensive search will be undertaken in the CENTRAL, MEDLINE, EMBASE, LILACS, PsycINFO, SCI-EXPANDED, CINAHL, SSCI, CPCI-S and CPCI-SSH to identify relevant trials. We will include randomised clinical trials assessing interventions theoretically based on guided self-determination or self-determination theory provided face-to-face or digitally by any healthcare professional in any setting. The primary outcomes will be quality of life, mortality, and serious adverse events. The secondary will be diabetes distress, depressive symptoms and adverse events not considered serious. Exploratory outcomes will be glycated haemoglobin and motivation. Outcomes will be assessed at the end of the intervention and at maximum follow-up. The analyses will be performed using Stata version 16 and trial sequential analysis. Two authors will independently screen, extract data from and perform risk of bias assessment of included studies using the Cochrane risk of bias tool. Certainty of the evidence will be assessed by GRADE. Discussion: Self-determination theory interventions aim to promote a more autonomous patient engagement and are commonly used. It is therefore needed to evaluate the benefit and harms according to existing trials. Systematic review registration: PROSPERO CRD42020181144.