As atmospheric CO2 emissions and the trend of urbanization both increase, the ability to accurately assess the CO2 budget from urban environments becomes more important for effective CO2 mitigation efforts. This task can be difficult for complex areas such as the urban–coastal Mediterranean region near Marseille, France, which contains the second most populous city in France as well as a broad coastline and nearby mountainous terrain. In this study, we establish a CO2 modeling framework for this region for the first time using WRF-Chem and demonstrate its efficacy through comparisons against cavity-ringdown spectrometer measurements recorded at three sites: one 75 km north of the city in a forested area, one in the city center, and one at the urban/coastal border. A seasonal CO2 analysis compares Summertime 2016 and Wintertime 2017, to which Springtime 2017 is also added due to its noticeably larger vegetation uptake values compared to Summertime. We find that there is a large biogenic signal, even in and around Marseille itself, though this may be a consequence of having limited fine-scale information on vegetation parameterization in the region. We further find that simulations without the urban heat island module had total CO2 values 0.46 ppm closer to the measured enhancement value at the coastal Endoume site during the Summertime 2016 period than with the module turned on. This may indicate that the boundary layer on the coast is less sensitive to urban influences than it is to sea-breeze interactions, which is consistent with previous studies of the region. A back-trajectory analysis with the Lagrangian Particle Dispersion Model found 99.83% of emissions above 100 mol km−2 month−1 captured in Summer 2016 by the three measurement towers, providing evidence of the receptors’ ability to constrain the domain. Finally, a case study showcases the model’s ability to capture the rapid change in CO2 when transitioning between land-breeze and sea-breeze conditions as well as the recirculation of air from the industrial Fos region towards the Marseille metroplex. In total, the presented modeling framework should open the door to future CO2 investigations in the region, which can inform policymakers carrying out CO2 mitigation strategies.