In 2012, Desmond was kidnapped and incarcerated by Abstergo Industries, a Templar organization, and forced into a machine called the Animus to relive the genetic memories of his ancestors, Aquilus and Altaïr Ibn-La'Ahad. It was Abstergo's aim to acquire a Piece of Eden called the Ankh and a map that detailed many Pieces of Eden spread across the Earth. Although Desmond did not lead them to the Ankh, he was reluctantly successful in helping them find the map. Following this, he managed to escape Abstergo with the help of Lucy Stillman, an undercover Assassin, and joined an Assassin cell in Italy, which consisted of herself, Shaun Hastings and Rebecca Crane. Utilizing an upgraded Animus of Rebecca's construction, Desmond relived the memories of Ezio Auditore da Firenze and Aquilus, in order to improve upon his newly obtained skills.
Eventually, with the knowledge gained from Aquilus' memories, Desmond and his fellow Assassins obtained the location of the Ankh, which was located in a shrine near the Villa Auditore.
Desmond lived with his family in a desert community, sometimes accompanying his father on trips through the barren wasteland surrounding their home. During one such trip, when they were watching an eagle in flight, Desmond was warned by his father to always be wary of "vultures", referring to the Templar Order.
In 2012, while serving drinks at the bar one night, Desmond was called over by a woman who told him that she had ordered martini from him ten minutes earlier, but that he had since forgotten all about her. As Desmond apologized and poured her a glass, the woman told him that she did not blame him and, in fact, envied him. When Desmond asked her how she envied him, she replied that his job was fascinating and eventually jokingly clarified that there was nothing more fascinating than the fact that he could stand there and see only her.
After his shift ended, Desmond and the woman walked along the streets of Paris. After the woman stated that she was interested in Desmond, she invited him to warm up at her place, which Desmond accepted in the condition that she tell him her name, prompting her to tell him to call her "Melanie".
At her appartment, Desmond offered to pour Melanie a drink, but she insisted that she would pour a drink for him instead. However, upon drinking from his glass, Desmond's head started spinning and he subsequently passed out.
Two days later, Desmond was sent to an Abstergo facility in Italy and was held captive for use as a test subject in the Animus, a device that could read the memories of people's ancestors through the "genetic memory" passed down through their descendants' DNA. Under the supervision of Dr. Warren Vidic, his assistant Lucy Stillman, and various Abstergo executives, Desmond was forced to relive the genetic memories of Aquilus, a Gallo-Roman member of the Assassin Order during the 3rd century. However, while reliving Aquilus' confrontation with General Gracchus in 259, Desmond desynchronized when Aquilus lost consciousness after being stabbed by Gracchus.
As Desmond emerged from Aquilus' memories, the executives argued that they were still not any closer to finding what they needed and one of them suggested getting rid of Desmond and finding someone else. Fortunately, Lucy interrupted them and insisted that Desmond's genetic memory offered enormous potential, which convinced the executives to discuss her proposition. After the executives left, Desmond, still unconscious, was taken to the bedroom provided for him and finally woke up as Lucy inserted a syringe of some kind into his arm. Confused and unable to remember how he got there, Desmond attempted to leave, only to be stopped by Lucy, who insisted that the best thing he could do was relax and regain his strength.
After Lucy promised to check up on him in an hour and left his room, Desmond's memories started returning and he finally managed to remember how Lucy, posing as "Melanie", had drugged and captured him. When Lucy returned to his room, Desmond grabbed her arm and demanded answers, prompting Lucy to reply that it was not her fault and she was not his enemy as well as informing him that his life there was hanging by a thread. When Vidic entered the room, Desmond demanded to know why he was brought there. However, instead of answering his questions, Vidic instead sedated Desmond once more and had him put back inside the Animus.
From that point on, Desmond was made to explore through the genetic memories of Altaïr Ibn-La'Ahad, a Syrian man who was a member of the Assassin Order during the High Middle Ages. Desmond relived Altaïr's assassination of Tamir, fighting off hypnotized Assassins with the aid of Malik Al-Sayf outside the fortress of Masyaf, and the final confrontation with Al Mualim. Eventually, Desmond achieved the Templars' goal and, through Altaïr's genertic memory, managed to provide them with a world map which projected the locations of many Pieces of Eden. Following this, the Abstergo executives ordered for Desmond's execution, but his life was saved by Lucy's intervention, as she asked them to keep Desmond alive in order to re-access his memories if necessary.