Due to current water shortages, the use of water from wastewater treatment plants (WWTPs) for horticultural crop irrigation is becoming increasingly common. This practice implies the risk of introducing pharmaceutical compounds into the food chain. The main aim of this work was to study the accumulation of two drugs in lettuces and their subsequent transfer into the food chain. The study focused on two widely used drugs, the anticonvulsant carbamazepine (CBZ) and the anti-inflammatory diclofenac (DCF), with different physicochemical properties in terms of their hydrophobicity and solubility in water. Three varieties of lettuce were selected and irrigated with water containing a mixture of the two pharmaceutical compounds at different concentrations. The results show the leaves presented the highest levels of uptake and greatest bioconcentration factors in the case of CBZ; however, in the case of DCF, by contrast, the highest uptake levels and greatest bioconcentration factors were observed in the roots. For CBZ, the Cleaf/Croot ratio was greater than 1, indicating good root-to-leaf drug translocation, whereas all Cleaf/Croot ratios were less than 1 for DCF. From the data acquired, our evaluation suggests that the concentrations of CBZ and DCF detected in the edible part of the lettuces do not imply any risk to human health.