Following his clerkships, Vignarajah practiced at Arnold & Porter in Washington, D.C., before serving as an Assistant United States Attorney for the District of Maryland, under Rod J. Rosenstein, and then as Chief of the Major Investigations Unit at the State's Attorney's Office for Baltimore City. In 2015, Vignarajah was named Deputy Attorney General for the State of Maryland. As Deputy Attorney General, Vignarajah was the lead author of statewide guidelines issued by the Maryland Attorney General to end discriminatory profiling by police, making Maryland the first state to answer former Attorney General Eric Holder’s call for states to issue guidelines on profiling. As a prosecutor, Vignarajah handled a number of notable cases in Maryland. He was responsible for prosecuting, among others, the alleged mastermind of a series of armed robberies that resulted in the murder of a Greek businessman in Baltimore; a former nonprofit board director who allegedly set a row home on fire with his mistress and her five-year-old son sleeping inside; and two alleged members of the Black Guerrilla Family who killed a 12-year-old boy and shot three other teenagers. Vignarajah has taught constitutional law, administrative law, and law and education as a member of the adjunct faculty at the University of Baltimore School of Law and the University of Maryland School of Law. He also teaches a course on crime policy at Johns Hopkins University. The first season of the podcast "Serial" focused attention on the 1999 murder of Baltimore teen Hae Min Lee. A high school classmate, Adnan Syed, was convicted of her murder in 2000. Vignarajah has handled multiple appeals filed by Syed's legal team. On 29 March 2018, Maryland's Court of Special Appeals upheld a ruling that Syed was entitled to a new trial. On 14 May 2018, Vignarajah appealed the ruling. On 8 March 2019, Maryland's Court of Appeals overturned the ruling and reinstated Syed's original conviction. While serving as Deputy Attorney General of Maryland, Vignarajah was covertly filmed by conservative political activist James O'Keefe for his organization, Project Veritas. Vignarajah was in a hotel room filmed giving a female Project Veritas reporter information about plans to side with the Environmental Protection Agency against Maryland Governor Hogan. The plan had not yet been announced to the public. A spokesperson for Maryland Attorney General Brian Frosh said that “No protected or confidential information was revealed in any discussions.” On September 14, 2017, Vignarajah declared his candidacy for Baltimore City State's Attorney as a Democrat.