During the trial, a friend of Mr. Syed said that he had heard him confess to the murder and accompanied him to the park to bury Ms. Lee’s body. But another student, who said she saw Mr. Syed in the library on the afternoon of Ms. Lee’s disappearance, was not called to the stand.

“Serial” debuted in 2014, featuring as its host Sarah Koenig, a former producer with the weekly public radio program “This American Life.” Its first season focused on whether Mr. Syed had received a fair trial. It was downloaded more than 100 million times and won a Peabody Award, turning the case into a topic of national conversation.

Image Mr. Syed and Hae Min Lee were in high school at the time of her disappearance. For many listeners, “Serial” raised doubts about his guilt. Credit... Syed family/HBO

In February 2016, lawyers for Mr. Syed argued in postconviction hearings that his original defense lawyer, Maria Cristina Gutierrez, who died in 2004, had been grossly negligent. They also presented new evidence, including testimony from the alibi witness.

Mr. Syed was granted a retrial in June 2016 by Judge Martin P. Welch of the Baltimore City Circuit Court, and that decision was upheld in 2018.

But things took a turn on Friday. The appeals court agreed that Ms. Gutierrez erred in failing to investigate the potential alibi witness but disagreed that this additional evidence would have changed the outcome of the case.

Mr. Syed had also tried to claim that his defense lawyer had failed to challenge cellphone location data that had been used by prosecutors in 2000. But the appeals court also rejected this on Friday, essentially because those claims were raised too late in the process.