The purpose of this work was to examine the level of major air pollutants and their future prediction in four major cities namely Karachi, Hyderabad, Nawabshah and Sukkur of Sindh province. The cause of pollution in the cities is due to population growth, unplanned urbanization, and congested transportation, commercial and industrial activities. The main parameters considered in this study were particulate matter (P.M) P.M2.5, P.M10, carbon dioxide (CO2), carbon monoxide (CO), oxides of nitrogen (NOx) and oxides of sulfur (SOx). A total of twenty locations were selected in Karachi, fifteen in Hyderabad, and ten each in Nawabshah and Sukkur. The selection of locations was made on the basis of traffic congestion, commercial activities and industrial establishments. The pollutants level was measured at different time intervals of the day such as morning, noon and evening on the basis of daily life human activities. The data was collected for a whole year with the help of PM meter, Ambient Air Quality meter, and Nitrogen and Sulfur Analyzers. OpenAir Model was used to determine the growth rate and future prediction of air pollutants. The predictions were made from year 2015 to 2050 with an interval of five years. Out of twenty selected locations of Karachi, four places namely Al Asif Square, North Nazimabad, Nursary and Star Gate were found more affected due to higher level of air pollutants where the average concentration of P.M2.5, P.M10, CO and CO2 were higher than permissible limits. Similarly, the level of P.M2.5, P.M10, and CO2 at Numaish Chorangi, Do Talwar and Clifton was higher than the permissible NEQS levels. The concentration of NOx was higher at North Nazimabad, Nursary and Star Gate locations and SOx were found lower than NEQS. It was revealed that the Sea View location was free from the air pollutants, may be due to lower traffic load and sea breeze which may transport air pollutants towards city. In Hyderabad city, the concentration of P.M2.5, P.M10, and CO2 at five locations namely Hala Naka, Hyderabad By-Pass, Nasim Nagar, City Gate and Market Tower were higher, whereas, theair pollutants level were lower than the permissible NEQS levels at all other locations. In Nawabshah city, the concentration of P.M2.5 was higher only at Mohni Bazar and P.M10 was higher than the permissible levels at all locations of Nawabshah city. The level of CO, NOx and SOx were found within permissible NEQS level at all locations of the city. In Sukkur city, the concentration of P.M2.5, P.M10, and CO2 was found higher at High Court Road, Eid Gah Road and Station Road than permissible levels at all five locations. The level of CO, NOx and SOx were within NEQS. OpenAir Model was used for determination of growth rate and future prediction of air pollutants. It was discovered from predicted model results that the growth rate of pollutants, such as P.M2.5, P.M10, CO2, CO, NOx and SOx varies from 1.0% to 4.0%, 0.5% to 1.5%, 1.0% to 6.0%, 1.0% to 4.0%, 1.0% to 4.0% and 1.0 to 4.0% respectively. It is concluded from the study that the level of P.M2.5, P.M10were found higher and CO2 and CO was almost within permissible levels in all selected cities, whereas, the level of NOx and SOx were found higher at most of the places in Karachi only. The model results predicted that concentration of pollutants will be at alarming level up to year 2050 if the growth rate of population, industrialization and transportation is continued. The findings of this work provide a baseline data and future predictions of air pollution level of four major cities of Sindh province. It will help the regulatory authorities to make effective policies for reduction of air pollutants and take measures for replacement of fossil fuels with environmental friendly fuels.