Background: Elucidating the links between the coronavirus disease (COVID-19) response, improvement in local air quality and potential health burden may leverage future air quality management. Speculation about improvement in environmental pollution amid COVID-19 outbreak is widespread. Pakistan observed national lockdown since March 15th, 2020 to prevent the transmission of COVID-19. The objectives of this study was to determine the change in particulate matter <2.5 microns and consequent change in the associated attributable fraction of morbidity and mortality in four major cities of Pakistan: Karachi, Lahore, Peshawar and Islamabad. Methods: Particulate matter <2.5 microns (PM2.5) levels before (from 01 Jan 2020 till 14th March, 2020) and during (15th March till 23rd April, 2020) the lockdown were obtained from fixed monitors from these cities. Pakistan’s health related statistics (for 2019) were obtained from Global Burden of Disease Study of Institute of Health Metrics (IHME), US. We estimated the attributable fraction of morbidity and mortality (using AirQ+) for ischemic heart disease (IHD), stroke, chronic obstructive pulmonary disease (COPD) and lung cancer before and during the lockdown and the differences thereof. Results: The average concentration of PM2.5 in four cities reduced from 155.18 µg/m3 to 96.15 µg/m3 (38.03% reduction). Consequently the average estimated reduction in morbidity and mortality in four cities were: IHD= ranged from 3.4% to 6.8%, higher for younger age group; stroke= ranged from 3.8% to 7.7%, higher for younger age group, higher for younger; COPD=8.3%; and lung cancer = 18.7%. Conclusions: The response to COVID-19 provides evidence for estimated reduction in morbidity and mortality of known cardiorespiratory diseases in four cities. Lockdown and social distancing provides an opportunity for environmental and health policymakers to delve into the social and economic activities that threatens the health of the humans. Smart interventions are needed to improve city environment and human health.