Bioretention is a popular solution for urban runoff (UR) control; however, there is scarce research about its adaptation to hot semi-arid climates, its efficacy in improving water quality therein, and the fate of UR pollutants in these devices. This work appraised the Agave salmiana incorporation, as an adaptation to semi-arid climates, in lab-scale bioretention columns. To assess the in vivo UR depollution potential of this xerophyte, six columns were packed with local filter materials and sandy loam soil. Three columns were covered with one A. salmiana specimen, while the other three were kept unvegetated. All columns were fed with synthetic urban runoff (SUR, containing known concentrations of the pollutants studied: N-NH4+, N-NO3-, PO43-, Pb, and Mn) for 12-h cycles (12 cycles were performed). The fate of UR pollutants was preliminarily assessed through geochemical modeling and then verified by mineralogical analyses. In the unvegetated columns, SUR mobilized Pb and Mn from the filter materials, which resulted, in some cycles, in concentrations of these metals in the columns' outlet higher than in the inlet. In the vegetated columns, A. salmiana enhanced the removal of N-NH4+, PO43-, Pb, and Mn and buffered the heavy metal mobilization from the filter materials into SUR. Moreover, A. salmiana actively contributed to the sequestration of these hazardous metals by forming secondary minerals (such as anglesite or Mn oxides) and to the N-NH4+ crystallization into arcanite, thereby constituting a promising adaptation of bioretention cells to hot semi-arid climates also improving UR quality.