Pretty Face begins with the main protagonist Masashi Rando, a high school student and karate expert who harbors an unrealized love for a fellow student, Rina Kurimi. One day, while returning home from a karate tournament in Hokkaidō, he is involved in a tragic school bus accident and is burned beyond recognition. One year later, Masashi awakes from a coma to find that he has been in the care of a talented (yet slightly deranged) surgeon named Jun Manabe. Masashi finds out his disfigured face had been reconstructed in the image of the girl he has a crush on. Not knowing what Masashi originally looked like, Dr. Manabe had used a photo in Masashi's pocket as the model for his reconstructive surgery.
Afterward, Masashi finds out that during his year long coma, he was mistakenly pronounced deceased, his parents moved away, and even his house was demolished. Once he has realized his old life is now gone, he breaks down on the sidewalk in front of the empty lot that was his former household. On his way back to Manabe's clinic, he runs into Rina by chance, and is mistaken for her missing twin sister, Yuna. After Rina takes him back to her house and presents him as Yuna, he lies about having amnesia in order not to arouse any sudden suspicions. Masashi wants Jun to change his face back to the way it was but has no picture of himself to help. He does get a picture of himself eventually but later, after seeing how much pain Rina experienced during the time her sister was gone, Masashi decides to impersonate Yuna for the time being until he can find the real Yuna and bring her back to the Kurimi family.
During this time, the story line chronicles various adventures that Masashi experiences through his new lifestyle with the Kurimi family while he searches for Yuna. Much of these stories include events in which Masashi's identity as a man comes close to exposure, however usually ending in him retaining his secret. Such adventures include being stuck in a hot spring bath with four girls, a health inspection, and various other activities. Most of these humorous adventures involve Rina's close friends, Yukie Sano, Keiko Tsukamato, and Midori Akai. As Masashi impersonates Yuna, he meets a number of reappearing characters such as Yuna's cousin Miwa Masuko, who for a period of time becomes suspicious of Masashi (impersonating Yuna) and threatens his new lifestyle for a while. However, realizing that the new Yuna shares the same compassion towards Rina as the previous one, she dismisses her suspicions and assumes that it is the same Yuna.
Another character that appears during Masashi's new lifestyle is Nozomi Ueda, a first year who shows interest in Masashi (impersonating Yuna). Nozomi is a strong girl who is very talented in kendo, and becomes attracted to Yuna (Masashi) because of his strength. Although never said directly, Nozomi is a lesbian who states numerous times that she does not like boys. Eventually, Masashi comes across Natsuo Kobayashi, a girl who met Masashi before and fell in love with him before his assumed death. As time passes, Natsuo finds out Yuna is actually Masashi. However, because of her love towards him, she keeps his identity a secret and helps Masashi out in numerous situations, hoping to win his love.
Throughout the story, Masashi's overall goal is to find the real Yuna and convince her to come back home so he can return to his real identity. His quest leads him to Otaru where he believed that the real Yuna would be since he found out that she had worked at a hair salon there. As he discovers to his dismay, she no longer resides there since the salon had been shut down. This trip to Otaru gives Masashi more of an idea of what Yuna is like, though does not help him find out where she is now.
Near the end of the manga, Yuna returns to her home. Meeting up with Masashi (still with Yuna's face), she discovers that he had impersonated her, and she initially becomes disgusted and horrified. However, after reading Masashi's diaries, she realizes how much he has cared for Rina and keeps his secret. Seeing Masashi's love for Rina, she entrusts him to continue impersonating her as she finishes her studies as a beautician. As the series ends, Masashi continues his life as Yuna Kurimi until the real Yuna finishes her studies.