Adnan Syed was convicted of murdering his former high school girlfriend, Hae Min Lee, in 2000 in Baltimore.
But a judge ruled on Thursday that Syed deserves another trial because his original lawyer failed to cross-examine an expert witness.
Millions of listeners tuned in to hear Syed's story through the podcast, broadcast online and over public radio.
Baltimore Circuit Judge Martin Welch said his lawyer should have questioned a mobile phone tower expert about the reliability of data that placed his mobile phone near the burial site.
His lawyers argued that his legal team did not contact a witness who saw him elsewhere at the time of the murder.
Asia McClain Chapman, an alibi witness, said she saw him at a library at the time of the murder.
After the ruling, Syed's lawyer Justin Brown said the new trial marked "an incredible victory" and said he would try to have his client released from prison while he awaits retrial.
This is his second attempt at a new trial. He was denied in 2014 after a judge determined his former lawyer's decision not to pursue Ms Chapman as a witness was not due to neglect.
Ms Chapman took the stand in February, and said she and Syed talked for 15 minutes in the library on the day of the murder.
She said she repeatedly tried to get in touch with Syed's defence team but was never contacted to be a witness.
A convicted murderer whose case was featured in hugely popular podcast Serial will receive a new trial.