Air pollution poses a substantial barrier to global environmental sustainability and citizen well-being. However, there is a lack of research that specifically examines the effects of short-term exposure to PM2.5 and its components on health outcomes in developing nations in Asia, regions often cited as having some of the most severe urban air quality issues globally. The present study evaluated the associations between PM2.5 components and hospital admissions (HA) and emergency room visits (ERV) for respiratory diseases in the megacity of Karachi, Pakistan. We measured PM2.5 constituents, including black carbon (BC) and ionic species (sulfate - SO42−; nitrate - NO3−; and ammonium - NH4+) at two sites (August 2008 to August 2009) in Karachi. The HA and ERV, respiratory disease outcome data, were collected from three local, large tertiary care hospitals. We assessed the lag structure of excess risk (ER) of the pollutants-outcomes association (0–6 single and cumulative lag days) using time-series quasi-Poisson models after adjusting for temperature, humidity, and day of the week. Among a total 13,827 patients, the highest ERs for all respiratory urgent care use (UCU) were observed for PM2.5 (10.3, 95% CI: 2.59%-18.59), NH4+ (9.58%, 95% CI: 1.50%–18.30%), air quality index (9.11%, 95%CI: 2.54%–16.09%) and SO42− (7.26%, 95% CI: 1.03%–13.87%) within 0–4 lag days. Additionally, patients with chronic obstructive pulmonary disease (COPD), tuberculosis (TB), or other pulmonary diseases and older or male patients were more vulnerable to these pollutants. This first study in Pakistan found that PM2.5 and its constituents were associated with respiratory HAs and ERVs for the inhabitants of the megacity of Karachi. These associations varied by different PM constituents, disease subtypes, age, and gender. Our results provide important information to policymakers for developing regulations for improving air quality and public health. Further studies are urgently needed in other developing countries to disentangle the air pollution health effects.