Matt arrived in Port Charles as a resident doctor at General Hospital under a fellowship sponsored by Nikolas Cassadine. He was initially suspected by nurse Nadine Crowell of being involved in a counterfeit drug ring, but later teams up with her to uncover the real criminals. During the course of the investigation, he is trapped in a fire and is hospitalized, where he is visited by Noah Drake. Their conversation is overheard by Patrick Drake, Noah's son, who is shocked to discover that Noah is Matt's father as well. Patrick works on developing a relationship with him, and convinces Matt to be his best man at his wedding to Robin Scorpio.
With Robin's help the brothers succeed in bonding, even though they remain very competitive especially in the operating room. This has led Matt into some predicaments: he was poisoned as a result of operating on a man that no one knew was transporting poison capsules in his stomach; and he was sued for malpractice after the mayor's mistress died during "routine surgery". Patrick and Robin were able to prove his innocence in the latter case by proving the death was actually a homicide, and with the help of Andrea Floyd, the mayor's wife, the malpractice suit was dropped.
Matt is currently still single despite his numerous attempts at flirting with various young women, most notably Maxie Jones. In December 2009, he briefly dated Lisa Niles. Maxie and Matt parted ways in early February due to irreconcilable differences, but got back together in 2011. During all of this, Matt and Patrick's ex Lisa tries to ruin Patrick and Robin's life by doing horrible things including tempting to kill Robin, and kidnapping Emma. This leads to Lisa taking Maxie, Spinelli, Robin, Patrick, and Steve hostage and shooting Spinelli. She is then stabbed with chemicals by Patrick and falls in a coma. She wakes up in October to terrorize Robin and Patrick, as well as their family and friends. During all this Matt has a party on a boat and since Maxie won't come, he invites Nurse Elizabeth Webber, who he kisses while being very drunk. During this a very drunk Matt kills Lisa while Maxie, who sneaked on the boat, sees and keeps quiet, while Matt doesn't remember. When Maxie finds out Matt kissed Liz, she gets very mad and tells chief-of-staff at GH, Monica Quartermaine, that Liz has been stealing drugs at GH. Elizabeth is fired and Matt breaks up with Maxie. In-order to get Matt back, Maxie tells Monica she lied and wins Matt back.
In Febuary 2012, Robin supposedly dies in a fire at GH leaving Maxie heartbroken. Maxie feeling depressed tells police she killed Lisa and Robin and goes to jail for 20 years. Spinelli then discovers Matt killed Lisa, but keeps quiet for Maxie. Spinelli kept quiet but never gave up on trying to find a way to free Maxie. He managed to doctor the photo of Matt killing Lisa enough so that it would free Maxie but not incriminate Matt. However things did not go as planned and Spinelli reveals that it was Matt and not Maxie who killed Lisa in a last ditch effort to save her. It works and Maxie is released but now Matt faced the murder charges. Maxie did not want Patrick and Emma to lose anymore of their family and she did not want to lose Matt so they decided to marry so that Maxie wouldn't be forced to give her incriminating testimony against him. Maxie was the only witness to Matt killing Lisa and her testimony surely would have put him away for a long time. Matt and Maxie marry and Matt goes free. However on their rather uneventful wedding night, Matt remembers the night he killed Lisa in full detail. Knowing that he would not be able to live with that over his head, he made plans to turn himself in. He went to the PCPD and confessed to Dante Falconeri, then he was given time to say goodbye to Patrick, Emma and Maxie before he was taken to Pentonville to serve a 5 year sentence for Lisa's murder.