Mafia matriarch Maria Santos appeared to be a very fragile old woman. Though she harbored an intense dislike for her daughter-in-law, Carmen, she doted on her grandchildren and they confided in her. However when Danny Santos tried to make the Santos family business legitimate, Maria finally showed her true colors. An old fashioned woman, Maria was adamant that the business her husband created would remain with the mob. In 1999, Maria was seemingly just a doting grandmother who was the first to learn that Danny was in love with his wife, Michelle Bauer. Although Danny had simply married Michelle to protect her from his mother (since Michelle was involved in the death of Danny's brother, Mick), he found himself falling in love with her. Though Carmen took an immediate dislike to Michelle, Maria urged her grandson to follow his heart. Later that year, Maria became concerned about Carmen's relationship with attorney Ben Warren, since she felt Carmen should honor the memory of her dead husband (Maria's son, Miguel). Realizing that her granddaughter, Pilar, hated Ben as well, Maria offered to help her granddaughter get rid of the attorney. So, Maria told Carmen that Ben was keeping his apartment so he could fool around with other women. Although Carmen refuses to believe it, Maria had planted seeds of doubt. Later, Maria informed Carmen that Ben and Pilar were having an affair. Distressed, Carmen went to confront Ben and upon seeing him with Pilar, she suspected the worse and shot him! Wanting to protect the family's reputation, and keep hidden her role in Ben's death, Maria provided Carmen with an alibi. However, when Michelle became a suspect, Danny was determined to discover the truth. Although they obviously disliked one another, both Maria and Carmen agreed that the person they need to concentrate on the most was Pilar, who was in danger of confessing all.

In 2000, the truth about Carmen's involvement in Ben's death was discovered and Carmen was sent to jail. However, after agreeing to testify against other mob families, Carmen was released and killed! With Carmen dead, Maria headed the family business and tried to convince Danny to take his proper place. She also formed an alliance with Danny's mother-in-law, Claire Ramsey, who, unbeknownst to everyone but Maria, had faked Carmen's death! Although Maria had initially supported Danny's decision to marry Michelle, it was becoming clear that Michelle was causing Danny to reconsider his role in the family business. In order to keep Danny from finding out the truth, Maria worked with a mobster named Carlos to set another mobster up for the crime. In addition to solving the mystery of who killed Carmen, it also had the added benefit of destroying Danny and Michelle's marriage since Michelle couldn't condone Danny's need to get vengeance for his mother's "murder." Later, Maria was overjoyed when Danny informed Maria that his marriage to Michelle was over and he was going to accept leadership of the family.

Meanwhile, Maria was adamant that the mob be involved in the San Cristobel construction project, and arranged several accidents, one injuring Josh Lewis. In addition, there were also rumblings that the mafia was involved in illegal immigration. Although Maria seemed insulted when Danny questioned her about it, her oldest grandson, Ray, a priest, wasn't so sure of her innocence. Not long after, Maria became suspicious about a book novelist Blake Marler was writing about the mob. Doing some investigating, Maria learned something startling--her late son, Miguel, had a mistress named Selena Davis before he died! Doing some more digging, she discovered that Selena may have given birth to Miguel's son! Enraged that she may have a grandchild whom she knew nothing about, Maria summoned Selena who confirmed that she had indeed given birth to Miguel's son, and when Carmen learned the truth, she killed Miguel. When Maria learned that Carmen learned the truth from Selena herself, she suddenly rose from her wheelchair and threatened Selena's life! Scared for her life, Selena fled town. Meanwhile, when Danny learnt the extent of Maria's illegalities and her role in faking Carmen's death, he took his place at the head of the family and barred her from seeing anyone.

In 2001, Maria was disappointed when Danny announced that the Santos family was going legit. When Maria begged Danny to return the family to its old ways, Danny refused, causing Maria to plan a secret meeting with Carlos. Maria then offered her younger grandson, Tony, the opportunity to head up the family. However, Maria knew that Danny wouldn't just walk away and allow the business to remain in the mob, and so she felt she had no choice but to place a hit on the grandson who had betrayed the family. Her plan was foiled, however, when Tony couldn't go through with the hit. Determined to have her way, Maria was set to kill both of her grandsons, but her assassins were overpowered and the plan failed. Danny then forced Maria and Carlos to flee to Cuba for their own safety since the FBI had a tape of them planning the hit on Danny. He then informed them that should anything happen to him or his family, he had arranged for the FBI to receive information informing them of the illegal activities of all the families

Maria returned to Springfield, soon after, with the help of the Sandoval family and would remain behind the scenes keeping an eye on her family. Of particular interest to her was Tony. Disapproving of Tony's relationship with Marah Lewis, Maria was fond of Catalina Quesada and, feeling that Catalina would be a welcome addition to the Santos family, manipulated Catalina into chasing after Tony. However Maria's feelings toward Catalina soured, in 2002, when she learned that Catalina was pregnant, thus trapping Tony into marriage. Not wanting Tony to be trapped by pregnancy to a manipulative wife like her son Miguel was, Maria decided that the wedding couldn't go on and ended Catalina's pregnancy by giving her poisoned tea. Catalina soon realized Maria had deliberately poisoned her, in spite of Maria's denials. Though she still claimed to be carrying Tony's child, Catalina later admitted to Maria that she lost the child and threatened to go to the feds if Maria tried to stop her marriage plans. Maria kept quiet, working on plan B. Maria arranged for Marah to find out Catalina wasn't pregnant, knowing that Marah would find Tony and tell him the news. Unfortunately, Marah didn't get to Tony in time and he married Catalina. When an angry Tony learned the truth, the next day from Ray, he went to the mansion to confront Catalina only to find her dead and Marah unconscious. Soon after, Maria suffered a stroke, leaving some to wonder if she killed Catalina. By early summer, Tony discovered that Maria had agreed to give Romeo Jones more power in exchange for Romeo killing Catalina and framing Marah. By the time Maria had returned from treatment, Romeo had confessed and was in prison, and even though Tony told her that he knew she was responsible for all of it, Maria denied any responsibility.

Late that year, Maria was shocked when Carmen confided to her that she had "killed" Danny. Maria coolly told her not to let anyone know and keep her feelings bottled up, lest she bring the entire family down. A few days later, Danny turned up alive and Carmen was arrested. Presumably with Carmen out of the way and Tony and Danny trying to go legit, Maria was once again in full control of the Springfield mafia. However, that assumption is now in question since Danny made some deals regarding the Santos operation. Presumably the Santos Mansion was sold and Maria Santos was sent out of Springfield for good for her crimes sometime in 2002.