The church was best known for being the site of a massacre by the aspiring priest, Sean O'Connell. He was driven to insanity by a witch's hex and brutally killed nine of his fellow seminary students before killing himself. The attic of the church was also used by Marcel Gerard as a residence and hide-out for Davina Claire following the uncompleted attempt of the Harvest ritual by the French Quarter Coven. The Church is also the birthplace of Hope Mikaelson and where Hayley Marshall was killed and initiated her transition into a hybrid.
- Main article: Davina's Room
For almost a year, Davina Claire lived in attic of St. Anne's Church, becoming her room to avoid the Harvest. In A Spirit Here That Won't Be Broken, Davina temporarily stayed in the attic after being resurrected.
- Sean O'Connell (killed by himself after he was hexed by Agnes)
- Nine seminary students (beheaded by Sean O'Connell)
- Agnes and three warlocks (killed by Elijah Mikaelson after their attempt to kill the unborn Hope Mikaelson)
- Sabine Laurent and three unnamed witches (killed by Davina Claire after they attacked her and Camille O'Connell)
- Kieran O'Connell (mercy-killed by Niklaus Mikaelson after being hexed and turned into a vampire).
- Unnamed warlock (decapitated by Niklaus Mikaelson to rescue Hayley and their child).
- Hayley Marshall (killed by Monique Deveraux after her childbirth, inadvertently transformed into a hybrid due to Hope's blood).
- Half of the parish in 1914 (killed by Kol)
- The Strix members (killed by Marcel Gerard)
- Dominic and the Hollow's Followers (killed by Sofya Voronova, and Klaus and Elijah Mikaelson)
- Hope Mikaelson (daughter of Klaus and Hayley, born as the French Quarter Coven held Hayley captive).
- Two unprecedented massacres have occurred inside St. Anne's Church.
- In 1914, Kol killed everyone in the church during Sunday services to ensure the death of a woman who was said to own the largest paragon diamond in New Orleans.
- Finn Mikaelson was captured by Hayley and Cami in the church and handed over to Klaus and Elijah at the compound.
- In For the Next Millennium, Marcel has established a fight club for his new vampires in St. Anne's Church, with Elijah as his sparring companion.
- In The Bloody Crown, Vincent has reclaimed the church to use it as a sanctuary open up to any supernaturals who are tired of fighting.
- Given that many witches have violently died here, it is most likely that it is marked with their power, thus making it a magical hot-spot; a source of immense power.
- In Voodoo Child, the Hollow and her followers take over the church.