Urban road dust pollution is a significant issue contributing to atmospheric pollution and storing contaminants such as heavy metals. This study aims to determine the heavy metal content and spatial distribution of road dust in Cairo, a city with increased anthropogenic activity, and to identify the possible main sources of individual metals using multivariate statistical analysis. Our study utilized inductively coupled plasma-mass spectroscopy (ICP-MS) to assess samples containing 15 heavy metal forms, including Chromium (Cr), Zinc (Zn), Arsenic (As), Cadmium (Cd), Mercury (Hg), Lead (Pb), Cobalt (Co), Bismuth (Bi), Nickel (Ni), Copper (Cu), Gallium (Ga), Strontium (Sr), Silver (Ag), Indium (In), Barium (Ba), and Iron (Fe). Various geo-accumulation indices, contamination factors, degree of contamination, pollution load index, enrichment factor, and pollution ecological risk index were used to evaluate the pollution degree. Results showed that the mean concentrations of the major heavy metals were 1798.55, 396.3, 410.22, 466.39, and 472.81 ppm for Pb, Bi, Ni, Cu, and Zn, respectively. The heavy metal spatial distribution was site-specific, with high Bi levels due to extensive industrial activities. The pollution degree decreased in the order of Bi > Hg > Cd > Zn > In > As > Cu. The heavy metals ranged from non-polluting to highly polluting. The study suggested that Bi substitutes Pb in the manufacturing industry as it poses lower risks. The toxic response (Tr) should be figured out regarding its significant enrichment.