The interrelationships between air quality, land cover change, and road networks in the Lagos megacity have not been explored. Globally, there are knowledge gaps in understanding these dynamics, especially using remote sensing data. This study used multi-temporal and multi-spectral Landsat imageries at four epochs (2002, 2013, 2015, and 2020) to evaluate the aerosol optical thickness (AOT) levels in relation to land cover and road networks in the Lagos megacity. A look-up table (LUT) was generated using Py6S, a python-based 6S module, to simulate the AOT using land surface reflectance and top of atmosphere reflectance. A comparative assessment of the method against in situ measurements of particulate matter (PM) at different locations shows a strong positive correlation between the imagery-derived AOT values and the PMs. The AOT concentration across the land cover and road networks showed an increasing trend from 2002 to 2020, which could be explained by urbanization in the megacity. The higher concentration of AOT along the major roads is attributed to the high air pollutants released from vehicles, including home/office generators and industries along the road corridors. The continuous rise in pollutant values requires urgent intervention and mitigation efforts. Remote sensing-based AOT monitoring is a possible solution.