Background: Understanding health trends and estimating the burden of disease at the national and subnational levels helps policy makers track progress and identify disparities in overall health performance. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides comprehensive estimates for Pakistan. Comparison of health indicators since 1990 provides valuable insights about Pakistan's ability to strengthen its health-care system, reduce inequalities, improve female and child health outcomes, achieve universal health coverage, and meet the UN Sustainable Development Goals. We present estimates of the burden of disease, injuries, and risk factors for Pakistan provinces and territories from 1990 to 2019 based on GBD 2019 to improve health and health outcomes in the country. Methods: We used methods and data inputs from GBD 2019 to estimate socio-demographic index, total fertility rate, cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years, healthy life expectancy, and risk factors for 286 causes of death and 369 causes of non-fatal health loss in Pakistan and its four provinces and three territories from 1990 to 2019. To generate estimates for Pakistan at the national and subnational levels, we used 68 location-years of data to estimate Pakistan-specific demographic indicators, 316 location-years of data for Pakistan-specific causes of death, 579 location-years of data for Pakistan-specific non-fatal outcomes, 296 location-years of data for Pakistan-specific risk factors, and 3089 location-years of data for Pakistan-specific covariates. Findings: Life expectancy for both sexes in Pakistan increased nationally from 61·1 (95% uncertainty interval [UI] 60·0–62·1) years in 1990 to 65·9 (63·8–67·8) years in 2019; however, these gains were not uniform across the provinces and federal territories. Pakistan saw a narrowing of the difference in healthy life expectancy between the sexes from 1990 to 2019, as health gains for women occurred at faster rates than for men. For women, life expectancy increased by 8·2% (95% UI 6·3–13·8) between 1990 and 2019, whereas the male life expectancy increased by 7·6% (3·5–11·8). Neonatal disorders, followed by ischaemic heart disease, stroke, diarrhoeal diseases, and lower respiratory infections were the leading causes of all-age premature mortality in 2019. Child and maternal malnutrition, air pollution, high systolic blood pressure, dietary risks, and tobacco consumption were the leading all-age risk factors for death and disability-adjusted life-years at the national level in 2019. Five non-communicable diseases—ischaemic heart disease, stroke, congenital defects, cirrhosis, and chronic kidney disease—were among the ten leading causes of years of life lost in Pakistan. Burden varied by socio-demographic index. Notably, Balochistan and Khyber Pakhtunkhwa had the lowest observed gains in life expectancy. Dietary iron deficiency was the leading cause of years lived with disability for both men and women in 1990 and 2019. Low birthweight and short gestation and particulate matter pollution were the leading contributors to overall disease burden in both 1990 and 2019 despite moderate improvements, with a 23·5% (95% UI 3·8–39·2) and 27·6% (14·3–38·6) reduction in age-standardised attributable DALY rates during the study period. Interpretation: Our study shows that progress has been made on reducing Pakistan's disease burden since 1990, but geographical, age, and sex disparities persist. Equitable investment in the health system, as well as the prioritisation of high-impact policy interventions and programmes, are needed to save lives and improve health outcomes. Pakistan is facing several domestic and foreign challenges—the Taliban's return to power in Afghanistan, political turmoil, catastrophic flooding, the COVID-19 pandemic—that will shape the trajectory of the country's health and development. Pakistan must address the burden of infectious disease and curb rising rates of non-communicable diseases. Prioritising these three areas will enhance Pakistan's ability to achieve universal health coverage, meet its Sustainable Development Goals, and improve the overall health outcomes. Funding: Bill & Melinda Gates Foundation. Translation: For the Urdu translation of the abstract see Supplementary Materials section.