This study delves into Green Infrastructure (GI) planning in Brindisi, Italy, evaluating its influence on urban air quality and thermal comfort. Employing an LCZ-centered Geographic Information System (GIS)-based classification protocol, the prevalence of LCZ 6 (Open low-rise) and LCZ 2 (Compact mid-rise) is highlighted. Despite generally low PM10 levels in Brindisi, intermittent NOx spikes surpassing WHO and EU standards pose health risks. Within LCZ 2, diverse GI interventions (green walls, hedges, trees) were tested, with green walls emerging as the most effective, albeit falling short of expectations, while trees exhibited adverse air quality impacts. LCZ 6 demonstrated enhanced air quality attributed to wind patterns, GI, and urban canyon improvements. Thermal comfort analysis consistently revealed positive outcomes across various GI types, reducing discomfort by a minimum of 10%. The study emphasized GI’s favorable comfort impact on sidewalks but cautioned against trees in street canyons with aspect ratios exceeding 0.7, heightening pollutant levels and implying increased exposure risks. Conversely, street canyons with lower aspect ratios displayed variable conditions influenced by prevailing regional wind patterns. In conclusion, the integrated assessment of LCZ and GI holds promise for informed urban planning, guiding decisions that prioritize healthier, more sustainable cities. This underscores the crucial need to balance GI strategies for optimal urban development, aligning with the overarching goal of promoting urban well-being and sustainability.