- Like many other hunters of the supernatural, Vayne's character concept is inspired by Abraham van Helsing, the protagonist from Bram Stoker's 1897 novel, Dracula.
- werewolves, are vulnerable to weapons made from silver. , is a reference to the belief that supernatural creatures, particularly
- Vayne is the only champion to currently have a health rating of 10.
- Vayne is the first champion to always have a quote play out when learning a skill.
- Vayne's quote "On wings of night." is similar to quote "On wings of fury."
- In the background of Classic Vayne's splash art, there is a tombstone labeled "URF" in reference to , and shovel.
- Vindicator Vayne is likely a reference to the Death Dealers from the Underworld film series.
- Vayne in her Aristocrat skin is wearing Steampunk-styled clothing.
- Heartseeker Vayne is a tribute to Valentine's Day.
- In her Heartseeker skin, is shown shot down in the background, and Vayne herself is reading a macaroni card made by him.
- In its Chinese artwork, Jack of Hearts Twisted Fate can be seen in the background.
- There is speculation that Vayne is secretly investigating the activities of  and the Black Rose organization.