Sea breezes are one of the most important weather processes affecting the environmental and climatic features over coastal areas, and the sea breeze from the Pearl River Estuary (PRE) has significant effects on the Pearl River Delta (PRD) region. We simulated a typical sea breeze process that occurred on 27 December 2020 in the PRD region using the Weather Research and Forecasting (WRF) model to quantify the effects of topography and city clusters on the development of the sea breeze circulation. The results show that: (1) the topography on the west coast of the PRD tends to block the intrusion of the sea breeze and detour it along the eastern part of the terrain in the southeast of Jiangmen. The depth of sea breeze along the position of the detour is increased by 120 m, the penetration distance is increased by 40 km, the maximum intensity of sea breeze decreases by ~0.4 m/s, and the time of maximum speed delays for 4 h. However, on the east coast, the topography promotes the sea breeze, resulting in an occurrence about 4 h earlier due to the heating effects. The depth and the speed of the sea breeze are increased by 466 m and 1.2 m/s, respectively. (2) Under the influence of Urban Heat Island Circulation (UHIC), the sea breezes reach cities near the coast an hour earlier and are later inhibited from propagating further inland. Moreover, a wind convergence zone with a speed of 3–5 m/s and a width of about 25 km is formed along the boundary of suburbs and cities in the PRD region. As a result, two important convergence areas: Foshan–Guangzhou, and Dongguan–Shenzhen are formed. (3) Overall, the topography has a more remarkable impact on the mesoscale wind field especially in the mountain and bay areas, resulting in an average speed disturbance of 2.8 m/s. The urban heat island effect is relatively small and on average it causes only ± 0.9–1.8 m/s wind speed perturbations in the periphery of two convergence areas and over PRE.