Background: The purpose of this systematic review is to study the changes in macronutrient composition of milk from Indian mothers in the past 100 years. Methodology: The systematic review was conducted in accordance with PRISMA protocol, and all records published between 1921-2021 were identified by searching databases like Google Scholar, ResearchGate, PubMed, Cochrane Database of Systematic Reviews. All observational, interventional or supplementation studies reporting any macronutrient (protein, fat, and lactose) in human milk of mothers of Indian origin, delivering term infants, were included. Any records on micronutrient composition, preterm mothers, data from other countries or methodological records were excluded. Milk was categorized into colostrum, transitional milk and mature milk and levels were summarized using mean. Findings: A total of 111 published records were identified on Indian mothers’ milk macronutrient composition in the past 100 years. Of these, 34 records were included in the final review. There seems to be an apparent decline in levels of fat and protein in colostrum in the last few decades. Protein and lactose levels in transitional milk also seem to have mildly reduced over time. No distinct changes were observed in the fat, protein, and lactose in mature milk. Various studies have reported associations between socio-economic status, maternal diet, maternal nutritional status, and other factors with macronutrient content in milk. Interpretation: Changes over time and some associations have been observed in this review. However, this review identifies a lack of good quality published data on macronutrient composition of Indian mothers’ milk. The declining trends of macronutrients, especially in colostrum needs to be studied in detail. There is a need for conducting well-designed, multi-centric studies on nutrient composition of Indian mothers using standardized methods of sampling and nutrient estimation for understanding the role of maternal diet, nutritional status, regional and ethnic differences. Funding Information: This research was funded by Abbott Nutrition. Declaration of Interests: DK and GV declare potential conflicts of interest as employees of Abbott Nutrition, the study sponsor. MY is an employee of Cognizant Technology Solutions, which provides statistical services to Abbott. SG as medical writer has supported the manuscript writing, reference screening, bibliography management and editing.