Lifetime cancer risk characterization of ambient PM-bound carcinogenic metals and polycyclic aromatic hydrocarbons (PAHs) were examined in the cities of Los Angeles (USA), Thessaloniki (Greece) and Milan (Italy), which share similar Mediterranean climates but are different in their urban emission sources and governing air quality regulations. The samples in Milan and Thessaloniki were mostly dominated by biomass burning activities whereas the particles collected in Los Angeles were primary impacted by traffic emissions. We analyzed the ambient PM2.5 mass concentration of Cadmium (Cd), Hexavalent Chromium (Cr(VI)), Nickel (Ni), Lead (Pb), as well as 13 PAH compounds in the PM samples, collected during both cold and warm periods at each location. Pb exhibited the highest annual average concentration in all three cities, followed by Ni, As, Cr(VI), Cd and PAHs, respectively. The cancer risk assessment based on outdoor pollutants was performed based on three different scenarios, with each scenario corresponding to a different level of infiltration of outdoor pollutants into the indoor environment. Thessaloniki exhibited a high risk associated with lifetime inhalation of As, Cr(VI), and PAHs, with values in the range of (0.97–1.57) × 10−6, (1.80–2.91) × 10−6, and (0.77–1.25) × 10−6, respectively. The highest cancer risk values were calculated in Milan, exceeding the US EPA standard by a considerable margin, where the lifetime risk values of exposure to As, Cr(VI), and PAHs were in the range of (1.29–2.08) × 10−6, (6.08–9.82) × 10−6, and (1.10–1.77) × 10−6, respectively. In contrast, the estimated risks associated with PAHs and metals, except Cr(VI), in Los Angeles were extremely lower than the guideline value, even when the infiltration factor was assumed to be at peak. The lifetime cancer risk values associated with As, Cd, Ni, Pb, and PAHs in Los Angeles were in the range of (0.04–0.33) × 10−6. This observation highlights the impact of local air quality measures in improving the air quality and lowering the cancer risks in Los Angeles compared to the other two cities.