To address the evidence gap in making effective language of instruction (LOI) decisions, we propose a systematic review of the role of LOI choices in education programs and policies on literacy outcomes in multilingual educational contexts in low- and middle-income countries (LMICs). Grounded in a multidisciplinary theory of change (ToC) describing what factors link LOI choices and literacy outcomes, we will gather, organize, and synthesize the evidence on the specific role of the three LOI choices described in the ToC (teaching in mother tongue [MT] with later transition, teaching in a non-MT language, or teaching in two or more languages at one time) and its impact on literacy and biliteracy outcomes. We will focus our systematic review and meta-analysis only on quantitative and qualitative intervention studies from LMICs as these have the highest relevance for decision making in multilingual LMIC contexts. We will also only include languages that are relevant and commonly spoken in LMICs. For example, we will likely include studies that examine Arabic to English transfer, but not Arabic to Swedish transfer.