River Elisabeth Wyles is a main character in To the Moon. She is Johnny's wife and she has Asperger's Syndrome, a disability on the autism spectrum. She first met Johnny at a carnival when they were children, where they agreed they would meet on the moon if they ever lost each other. This is the reason that Johnny's dying wish is to go to the moon.

River passed away before the main events of the game begin. She was diagnosed with a late-stage terminal illness and refused treatment because the cost would prevent Johnny from finishing the house they were building that overlooked the lighthouse, Anya. As a child, she thought stars were lighthouses, spread out across the sky. River believed they lived a lonely existence, far from the other stars, so she wanted to "befriend" one in her lifetime so that it wouldn't be lonely. (This could also stand as a metaphor for River, although it has not been yet proven.)

River has a very strong attachment throughout her life to a stuffed platypus that was given to her by Johnny during the carnival. After Johnny confesses that he first started dating her because Johnny wanted "someone different", River realizes that he lost his memory of their first encounter at the carnival and begins to make various origami rabbits in an attempt to remind him of the night they met. (Note that this making of paper rabbits is also a way to release anxiety, and is seen as a "symptom" of Asperger's. Another common trait River experiences is a difficulty in expressing or articulating one's thoughts and emotions by "normal" means, such as direct conversation, making it somewhat tough for River to remind John of their first encounter. After asking Johnny if he ever created shapes from the stars, they used the moon and stars in the sky to create a constellation resembling a rabbit. She even creates one with blue paper for the head and feet and yellow for the torso, as it resembles the yellow moon that makes up the belly of the rabbit constellation (additionally, her wedding dress was blue and yellow). This was her best attempt in order to reconnect Johnny's memories for him.