Nanoscale devices exhibiting memristive properties show great potential in a plethora of applications. In this work, memristive nanowires are presented for the first time as ideal candidates for absolutely novel, ultrasensitive, highly specific and selective drug-biosensors, also paving the way for real-time monitoring applications, in coupling with the restoration properties of DNA-aptamers. The hysteretic properties exhibited by the hereby-presented special nanodevices, modified via surface treatments, are leveraged along the complete cycle consisting of DNA-aptamer immobilization, target binding, and DNA-aptamer regeneration for successful and effective detection of Tenofovir, an antiviral drug for HIV treatment, in buffer as well as in non-diluted human serum. This results in ultrasensitive, label-free monitoring of the therapeutic compound with a limit of detection of 3.09 pM in buffer and 1.38 nM in full serum. These LODs demonstrate 10 times higher sensitivity for the in-buffer drug detection, and twice better performance for drug sensing in full human serum, ever obtained. The selectivity of the memristive biosensor for Tenofovir detection was verified through both positive and negative controls in full human serum. In addition, the DNA-aptamer regeneration character is portrayed for the first time through a memristive effect, and scanning electron microscopy throws more light on the binding mechanism efficiency through the variation of the nanodevice surface properties at the nanoscale. The results presented in this work demonstrate that the coupling of the memristive effect and aptamer regeneration provides the best ever realized nano-biosensor for drug detection also in full human serum.