Open disposal is the most common technique used for municipal solid waste (MSW) management due to the absence of sanitary landfills in Pakistan. The major cities and small towns in Pakistan have become a showcase of negligence and mismanagement of MSW, which results in deterioration of the environmental and social-life quality. Moreover, research has proved that inefficient handling (disposal) of MSW results in uncontrolled emissions of greenhouse gases (GHGs), mainly methane, and adds a significant share in global climate change. This study aims to estimate methane emissions from MSW disposed of at dumpsites and compare the GHG mitigation potential of different landfill strategies in specific climate and waste compositions in Karachi. The GHG estimations are based on lab-scale investigations conducted by simulating landfill conditions through the landfill simulation reactor (LSR) experiment. The synthetic MSW sample representing the composition of MSW generated in Karachi was used in the LSR experiment. Environmental sustainability and GHG mitigation potential of different landfilling strategies was evaluated by analyzing gas formation potential (GP21) and respiration activity (RI4) at the end of the experiment. This study revealed that the quantity of solid waste annually disposed of at dumpsites in Karachi possesses the potential to release about 3.9 Mt CO2-eq. methane (with specific methane potential of 1.8 tCO2-eq./tonne DM disposed) due to the biological decomposition of the organic fraction. Results show that the fresh waste disposed of at landfill sites in Karachi possesses about 92% and 94% higher GP21 and RI4, respectively, than the German allocated criteria for mechanically and biologically treated (MBT) waste for landfills Furthermore, sanitary landfills with post-aeration conditions showed higher GHG mitigation potential and low biological activity in the waste. The second highest GHG mitigation potential and lowest biological activity of the waste was noticed from bioreactor landfills with post-aeration conditions. The third number in GHG mitigation and reduced waste activity was noticed in the waste sampled from bioreactors without aftercare approach. The least GHG mitigation potential was noticed from the uncontrolled waste dumping (existing) approach with high residual gas potential and respiration index level. This lab-scale landfill simulation study can provide baseline data for further research and planning the development of new sustainable landfills in Karachi, Pakistan and in the region.