On the first day of the World Championships, Manuel anchored the women's 4x100-meter freestyle relay to a gold medal alongside Mallory Comerford, Kelsi Worrell, and Ledecky. She split a very fast 52.14 to anchor the team to a new American record time of 3:31.72. Manuel picked up her second gold of the meet when she anchored the mixed 4x100-meter medley relay with a split of 52.17. Together with Matt Grevers, Lilly King, and Caeleb Dressel, the team broke the world record in a time of 3:38.56. Manuel's first individual event of the meet was the 100-meter freestyle, where Swedish swimmer Sarah Sjöström was widely considered the favorite to win since she had broken the world record while leading off the 4x100-meter freestyle relay on the first night of the World Championships. In similar fashion to the previous summer at the Olympics, Manuel upset the favorite by coming from behind to win the 100-meter freestyle with an American record time of 52.27, out touching Sjöström by just four-hundredths of a second. The day after, she won her fourth gold medal in the mixed 4x100-meter freestyle relay, where she split 52.18 on the anchoring leg. Alongside Comerford, Dressel, and Nathan Adrian, they set a world record of 3:19.60. On the last night of the meet, Manuel swam the finals of both the 50-meter freestyle and the women's 4x100-meter medley relay. Touching in a bronze-winning time of 23.97, she set the American record and became the first American woman to break the 24-second barrier in the 50-meter freestyle. Manuel then anchored the women's 4x100-meter medley relay to a winning time of 3:51.55. The team of Kathleen Baker, King, Worrell, and Manuel broke the 2012 world record of 3:52.05 set by Missy Franklin, Rebecca Soni, Dana Vollmer, and Allison Schmitt.