Background Atherosclerotic cardiovascular diseases (ASCVD) are on the rise in low and middle-income countries attributed to modern sedentary lifestyle and dietary habits. This has led to the need of assessment of the burden of at-risk population so that prevention measures can be developed. The objective of this study was to assess ten years risk assessment of ASCVD using Astro-CHARM and Pooled Cohort Equation (PCE) in a South Asian sub-population. Methods A total of 386 residents of all six districts of Karachi with no ASCVD were enrolled in the study through an exponential non-discriminative referral snowball sampling technique. The inclusion criteria consisted of age 40 years or above and either gender. Study participants were enrolled after obtaining informed written consent and those study participants who were found to have either congenital heart disease or valvular heart diseases or ischemic heart disease were excluded from the study based on initial screening. For the calculation of 10 years risk of ACVD based on Astro-CHARM and PCE, the variables were obtained including medical history and coronary artery calcium and C-reactive protein measurements. Results Mean estimated 10-year risk of fatal or non-fatal myocardial infarction or stroke as per the Astro-CHARM was 13.98±8.01%, while mean estimated 10-year risk of fatal or non-fatal myocardial infarction or stroke as per the PCE was 22.26±14.01%. Based on Astro-CHARM, 11.14% of the study participants were labeled as having high risk, while PCE estimated 20.73% of study participants as having high risk of ASCVD. Conclusion Despite the fact that our findings showed substantial differences in ten-year risk of ASCVD between Astro-CHARM and PCE, both calculators can be used to develop a new population and specific risk estimators for this South Asian sub-population. Our study provides the first step towards developing a risk assessment guided decision-making protocol for primary prevention of ASCVD in this population.