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Abstract Introduction Explanations for health inequalities include material, behavioural and psychosocial pathways. Social relationships are an important determinant of health, and research has consistently found that a lack of support networks may diminish favourable health outcomes. There is some evidence that social network structures, partly shaped by socioeconomic factors, contribute to health inequalities. This protocol will summarise the systematic review process. Methods and analyses The Systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. An electronic database search of MEDLINE, Embase Classic + Embase and PsychINFO using the OvidSP platform will be undertaken. Databases will be searched from the earliest date of entry until 10 June 2022. Articles that have quantitatively assessed the role of social relationships in mediating or moderating health inequalities will be included and any health outcome (mental/physical) will be considered. The database search will be supplemented by reference list screening of all relevant full-text articles identified through the search. Two independent reviewers will be responsible for screening of articles, data extraction and assessment of bias. Observational studies will be risk assessed for bias using a modified version of the Newcastle-Ottawa Quality Assessment Scale, and intervention studies will be assessed using the revised Cochrane risk-of-bias tool. It is anticipated that the eligible studies will be highly variable; therefore, a meta-analysis will only be considered if the available data of the selected studies are similar. If the studies are too heterogeneous, a narrative synthesis of the extracted data will be presented. Conclusion The results of the systematic review will examine the link between social relationships and health inequalities. The findings of the review will identify gaps in knowledge where further research is needed. Systematic review registration PROSPERO CRD42020181706