Melinda Uy is a billionaire widow whose life is a rags-to-riches story. The daughter of a Chinese immigrant and a Filipino small businessman, Melinda had been a victim of discrimination in the local Chinese community, being only half-Chinese.  Melinda was only in her late teens when she got married to Alfonso Uy, the scion of the wealthy Uy clan. But Alfonso’s parents frown upon the marriage, believing that it is cursed. Disappointed with Alfonso’s choice of wife, they disinherit him.

The couple strikes out on their own, starting a small business from scratch as they raise a family of their own. . But, as Alfonso’s parents predicted, a string of misfortunes hounds the marriage. The business they put up enjoys only a brief period of prosperity before it goes bankrupt. And just when they are slowly recovering from their financial woes, fire breaks out in their residence, wiping out everything they own. But the worst is yet to come. By this time, the couple already have four children, namely Carol, the eldest, followed by Stephanie, Audrey and Walden.  But the kids would not enjoy the company of their father for long. Unexpectedly, Alfonso dies of a massive stroke.

A widow at a young age, Melinda along with her children is compelled to live with her in-laws who maltreat her. One day, Melinda, along with eldest child Carol, returns to the house of her in-laws from a visit to her mother. Melinda is shocked to find out that she is no longer welcome. She is driven away after a failed attempt to take Carol away from her. 

Little Stephanie, Audrey and Walden are left behind in the house of the in-laws. Melinda’s efforts to take custody of them come to naught as her in-laws manage to hide the children from her. Melinda goes through hell in her attempts to take back her children. But Melinda’s determination is no match to the power of her in-laws.

Short of giving up, Melinda vows to someday take back her children as she channels her efforts to succeed financially, while continually monitoring the condition of her three children from afar.

Growing up away from her mother, Stephanie learns to hate Melinda, thanks to the constant brainwashing of Aunt Olive who finds pleasure in demonizing Melinda. 

Melinda experiences a good turn of fortune in the years that follow. She becomes one of the most wealthy and powerful women in the business community. At about this time, the fortunes of her once powerful in-laws are on the decline.

But Stephanie, now a young adult who’s already taking over the businesses of her aunt Olive and grandparents, is about to get married to a shady character, the dashingly handsome Daniel Chan.

Melinda is now ready to revive her claim on her three children, but years of separation make it seem impossible for her to win back their love. But the news of Stephanie’s marriage to Daniel Chan alarms Melinda, forcing the powerful widow to act, thus putting her on a collision course with Olive and the in-laws.

This time, Melinda is determined to succeed in having back her grown-up children. And this time, events transpire to make Melinda prove to her estranged children how much she really loves them.

Mano Po 6 Metro Manila Film Fest Awards