The effect of metals on the photosynthetic activities and epidermal polyphenol content of Prosopis glandulosa and Prosopis juliflora leaves was investigated by the tissue tolerance test. Foliar tissues of Prosopis glandulosa and Prosopis juliflora were incubated with Cd2+ (0.001 M) or Cu2+ (0.52 M) concentrations for 96 h. The results showed that significant reductions (p < 0.05) of photochemical efficiency in P. juliflora leaves were found after 96 h of exposure to 0.52 M Cu2+ compared with Cd-treatments and controls. In contrast, P. glandulosa leaves showed a progressive increase on photochemical efficiency at 72 h after Cu-treatment. The results also showed a significant decrease (p < 0.05) of epidermal polyphenols in P. juliflora leaves after 24 h of exposure to 0.52 M Cu2+ compared with Cd-treatments and control leaves. On the other hand, the values of leaf epidermal polyphenols observed in P. glandulosa exposed to copper and cadmium did not show any difference with respect to control. These findings are very important and suggest that these compounds could be considered as a protection mechanism of P. glandulosa when is treated with these heavy metals. Finally, the results of bioaccumulation showed that the copper concentration in P. glandulosa was higher than the values detected in P. juliflora Nevertheless, the cadmium concentration in foliar tissues of P. juliflora was significantly higher than P. glandulosa after 96 h of exposure to Cu2+ or Cd2+. Therefore, future studies are necessary to elucidate the effects of heavy metals on the biosynthesis of flavonoids and participation of these compounds in the reduction of metal toxicity in Prosopis species.