Out of pocket payment (OOPP), is the major health financing mechanism in South Asia region. With the rising burden of non-communicable diseases (NCDs), the region is facing a high financial burden. However, the extent and nature of economic impact caused by treatment and management of NCDs at the household level is yet unknown. Method We conducted a systematic review using Medline and Embase databases. Only peer-reviewed quantitative studies published between January 2000 to December 2016 assessing OOPP or catastrophic health expenditure or impoverishment or financial coping strategy due to at least one of the four major NCDs—cardiovascular diseases(CVDs), diabetes, cancer, chronic respiratory disease in South Asia region was included in the review. The review is registered in PROSPERO no: CRD42017059345. Results A total of 21 studies (of 2693 records identified) met the inclusion criteria. The economic impact was most frequently studied in CVDs and in terms of OOPP. The studies collectively indicated high OOPP, higher likelihood of catastrophic expenditure and impoverishment for inpatient care for these major NCDs which was visible in all income levels. Borrowing and selling off assets were the most common forms of coping strategies adopted and varied inconsistently between urban and rural households. The true extent of the economic impact, however, remains difficult to determine due to methodological heterogeneity regarding outcomes reported and measures employed for calculation of OOPP, catastrophic expenditure, and impoverishment across these four major NCDs and between nations. Conclusion The economic impact due to treatment and management of CVDs, diabetes, cancer and chronic respiratory diseases among households in South Asia seems dire. Given the lack of sufficient evidence the review stresses the need for further research in the region to develop evidence-informed nationally tailored prepayment mechanisms covering NCDs to reduce economic vulnerability and standardization of tools measuring the economic impact for generating comparable estimates.