Born at an unrevealed location in California, Betty Ross was the only child of high ranking Air Force General Thaddeus E. "Thunderbolt" Ross and his wife Karen. After the death of her mother, Betty was emotionally abandoned by her father and sent to boarding school.

After finishing school, Betty returned home to find out that her father was the head of the U.S. Defense Department's top secret Gamma Bomb Project at an undisclosed desert base in Nevada. It was there that Betty met and fell in love with her future husband Dr. Robert Bruce Banner, the designer of the G-Bomb and supervisor of the project. Their romance was much to the dismay of General Ross, who believed Banner to be both physically and emotionally inferior.

During the G-Bomb's first test, Banner selflessly rushed to the rescue of an ignorant teenager, Rick Jones, who had wandered onto the testing ground as the countdown ticked inexorably toward zero. Irradiated by the radiation of a full-force Gamma Bomb, Banner was transformed into a monstrous Hulk of green muscle mass. Although Banner managed to keep his double identity secret, his attempts to cover up his activities as the Hulk led to General Ross and his head security chief, Major Glenn Talbot, to suspect Banner of being a traitor. Talbot also fell in love with Betty, but she remained faithful to Banner, even in the wake of his secret being exposed.

Later, Banner's "Professor" Hulk personalty manifested, which allowed him to remain fully coherent, retaining his intelligence when he transformed. With this change, Banner finally attained consent from General Ross to marry Betty. However, during the ceremony, the Hulk's enemy, the Leader, seeking vengeance for his previous defeat, fired radiation at Banner reverting him into a savage, much more monstrous Hulk. The enraged Hulk then tore apart the house where the wedding had been held, and all hopes of a wedding were destroyed.

When the Hulk was later confined to the microverse, he began a romantic relationship with their queen Jarella. Betty eventually learned of Bruce's adoration of Jarella and although she still loved him, she returned Talbot's affection and they were soon married. While Betty was on her honeymoon, General Ross was captured by the Soviet scientist Gremlin and sent to a Soviet prison. Talbot took part in a mission to rescue General Ross, only to be captured. After escaping, General Ross and the other Americans involved in the mission mistakenly believed that Talbot had been killed. Informed of this news, Betty suffered a nervous breakdown. In this condition, she was easily captured by MODOK, leader of the organization A.I.M., and turned into the insane creature known as the Harpy. After numerous battles with the Hulk, the transformation was finally reversed, restoring Betty's humanoid form as well as her sanity.

Eventually, it was discovered that Talbot was still alive and he was rescued. Shortly after his return home, Betty realized that she still loved Banner, and they were soon divorced, fueling Talbot's hatred for Bruce and his attempts to kill the Hulk. Talbot later died trying to destroy the Hulk.

Bruce and Betty went through many trials, including a period when Banner disappeared. Upon his return, the Hulk was subjected to a process that split him and Banner into separate beings for a short time. Banner took full advantage of this, marrying Betty and attempting to lead a normal life. After Banner and the Hulk were once again merged, Betty's father Gen. Ross died in the process of saving both Betty and the Hulk.

The Hulk's multitude of personalities were eventually merged into one and he was propositioned by the Hero Agamemnon to join his group the Pantheon. During the Hulk's long tenure with the Pantheon, his relationship with Betty faltered but eventually grew stronger and endured. After the group turned on its leader, the ensuing battle led to the Hulk coming under S.H.I.E.L.D.'s custody and Betty's hospitalization.

Later, Betty learned that her long association with the Hulk had left her dying from over exposure to gamma radiation. Abomination, seeking retribution after a massive defeat at the hands of the Hulk, learned of Betty's present state and used his own gamma-radiated blood for the transfusion, poisoning her, and leading to her death.

However, after a period in which Bruce was mentally tortured by Nightmare, Betty was apparently resurrected. After undergoing plastic surgery and being given new identity by a conspiracy fronted by the Leader, Betty appeared to wash up on an island.