Prior to the outbreak, River Street was a regular city street in Savannah. The River Street Streetcar line ran along it, and a number of shops and restaurants were located in restored nineteenth-century warehouses on the road. The street was often used for celebrations, such as Savannah's St. Patrick's Day celebrations.
When the group arrives in Savannah, Kenny decides that their first course of action should be to head for River Street and look for a boat. However, they are soon attacked by walkers and forced to hide in a nearby mansion. After the walkers dissipate, Kenny and Lee head to River Street while the remaining group members continue to search the house.
Upon reaching River Street, Kenny and Lee are shocked to find the docks empty, save for a few wrecked boats. Kenny checks to see if he can fix one of them while Lee explores the street. He discovers a menacing pile of walkers at one end, and a sign reading "KEEP OUT". He then uses a telescope to search the other side of the river, but to no avail. However, he spots a mysterious figure climbing down a building at the end of the street, quickly hides with Kenny. The two decide to confront the stranger, thinking that he or she might be the one on the walkie-talkie. After a short struggle that ends with Clementine's surprise arrival, the stranger reveals herself to be Molly, a scavenger and the one who has been ringing the bells around Savannah. She explains that she does so to draw walkers away from whatever area she plans to explore. She also explains that the pile of bodies was placed there by Crawford, a community of ruthless survivors who have picked the city clean of supplies. Suddenly a group of walkers show up, trapping the group. Molly parkours up an alley, and is about to leave the others behind when Clementine convinces her to help them. Clem and Kenny are brought up, but Lee is left on the street. He hurriedly climbs down a storm drain to escape.
Later, when Lee is bitten and Clementine is kidnapped, anyone who stays with the boat says that they will prepare it and bring it to River Street while the others look for Clem.
After Kenny's disappearance and Ben's death (determinant), Lee, Omid, and Christa arrive on the roof of a building on River Street, a block away from The Marsh House. When Lee is separated from the couple after the Maccabe Imports sign collapses, he can tell them to look along River Street for a boat. He then descends to the street and fights his way through a herd of walkers to the hotel.
After Lee rescues Clementine, the pair covers themselves in walker guts and attempts to walk back through the herd to River Street. Unfortunately, Lee collapses before they make it, and Clementine drags him to safety in a nearby jewelry store.