Rapid urban developmental growth is a heated debate worldwide due to environmental challenges. This research has examined the spatiotemporal trend of informal built-up growth in Karachi city. Using a geo-information system, the past twenty years (2000–2020) trends of informal built-up growth are examined. For attaining the research objectives, geo-referenced high-resolution maps and satellite images are used for accuracy based spatial data. Karachi is divided into five different land use and land cover (LULC): formal built-up, informal built-up, vacant, water bodies, and green spaces. Spatial data of informal built-up growth change of five different years, 2000, 2005, 2010, 2015, and 2020 are generated through acquired maps digitization using ArcMap. Subsequently, the gains and transfers of Karachi's informal built-up growth based on five years 2000–2005, 2005–2010, 2010–2015, and 2015–2020 are analyzed using the Land Change Modeler (LCM) in IDRISI software. Also, land use land cover changes (LULCC) are predicted for the next 40 years (2020–2060) using the integrated Cellular Automata Markov (CA-Markov) simulation model in IDRISI. The results revealed that Karachi's built-up is expanding rapidly. Land conversion into the informal built-up area is alarming, as it has changed from 144.31 km2 to 217.19 km2 with 72.88 km2 in the past twenty years (2000–2020) and has occupied green and agricultural land. Most informal built-up areas have transitioned from vacant (71.01 km2) land use land cover (LULC). The informal built-up area could expand from 217.19 km2 to 317.63 km2, with about 100.44 km2 up to 2060. The planned and unplanned development will be towards the city's East (E) direction and will convert and ruin agriculture and vacant land. The present study provides suggestions to urban planners, administrative authorities, and policymakers to control informal growth and achieve sustainable development goals in developing countries.