Freshman university student Josh Wheaton attends a philosophy class, where the uncompromising Professor Radisson requires all students to submit a signed statement that the "God is dead" and never existed. When Josh refuses due to his own Christian beliefs, the Professor challenges him to defend his position that his god, Yahweh, is real, leading to a series of confrontational presentations between himself and the professor, with the class as jury. Josh's plans to go to law school depend on not failing this class. Josh's girlfriend urges him not to throw away his future with this pointless act of defiance. At the same time, Pastor Dave and African missionary Jude attempt to leave town on a trip, but are hindered by comical accidents. Student Ayisha is at odds with her father's conservative religious principles. Businessman Mark acts cynically towards his mentally ill mother, while his journalist girlfriend receives bad news from a doctor.
Radisson gives Josh twenty minutes at the end of the first three lecture sessions to argue that God exists. In the first two debates, Radisson has counter arguments for all of Josh's points. Josh's girlfriend Kara (Cassidy Gifford) tries to convince him to either drop out of class or follow Radisson's rules, fearing that standing up to Radisson will jeopardize their academic future, but she eventually breaks up with him when he refuses to disown his belief in God. Ultimately, it comes down to the third and final debate between Radisson and Josh, who again both make compelling points. Josh then halts his line of debate to pose a question to Radisson: "Why do you hate God?" After Josh repeats the question twice more, Radisson explodes in rage, confirming he hates God for his mother's death that left him alone despite his prayers. Josh then casually asks Radisson how he can hate someone that does not exist. In the end, Martin (Paul Kwo), a foreign exchange student whose father had encouraged him not to convert to Christianity so he can stay focused with the class, stands up and says "God's not dead." Almost the entire class follows Martin's lead, causing Radisson to leave the room in defeat.
Against the backdrop of the debates, a series of peripherally related subplots develop. Radisson dates Mina (Cory Oliver), an evangelical whom he often belittles in front of his fellow atheist colleagues. Her brother Mark (Dean Cain), a successful businessman and atheist, refuses to visit their mother, who suffers from dementia. Mark's girlfriend, Amy (Trisha LaFache), is a left-wing blogger who writes articles critical of Duck Dynasty. When she is diagnosed with cancer, Mark dumps her. A Muslim student named Ayisha (Hadeel Sittu) secretly converts to Christianity. However, when her brother caught listening to the passage of 1 Corinthians 15 on her iPod, she is ultimately disowned by her infuriated father when he finds out.
After the final debate, Josh invites Martin to attend the Newsboys concert that is in town. Radisson reads a letter from his late mother, and is moved to reconcile with Mina. Amy confronts the Newsboys in their dressing room, only to admit that she wants to get to know God. While Radisson is on way to find Mina, he is struck by a car and fatally injured.. Reverend Dave (David A.R. White) witnesses the incident just couple meters away. Reverend Dave finds him and guides him in becoming an evangelical Christian as he dies. Mark at last visits his mother, only to taunt her; she responds that all of his financial success was given to him by Satan.
As the film ends, the Newsboys play a video clip of Willie Robertson congratulating Josh. The Newsboys then play their song "God's Not Dead", dedicating it to Josh.