The church was best known for being the site of a massacre by an aspiring priest, Sean O'Connell, who 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 failed first attempt at the Harvest ritual by the French Quarter Coven.
- 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.
- 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 and three unnamed witches (killed by Davina Claire after they attacked her and Camille)
- 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).
- Half of the parish in 1914 (killed by Kol)
- The Strix members (killed by Marcel Gerard)
- Hope Mikaelson (daughter of Klaus and Hayley, born as the French Quarter Coven held Hayley captive).
- St. Anne's Church was the setting of the massacre in which Sean O'Connell, Camille's twin brother killed his fellow seminary students before proceeding to kill himself. This is the second unprecedented slaughter to have occurred inside the church.
- Before his death, Sean worked here while he was training to be a priest.
- Father Kieran died here.
- Hope Mikaelson was born here.
- Hayley died as a werewolf in this church before awakening in transition as a hybrid after dying with her daughter's blood in her system.
- 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. They needed the diamond so that his witch associates, Mary-Alice Claire and Astrid Malchance could finally transform one of the silver daggers that neutralize Original vampires into a gold one that would work against Klaus.
- 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.