The drama explores themes in Christianity, culture and Philippine mythology such as aswang (fearsome, vampire-like shape-shifters), and tagapagbantay, the Philippine version of guardian angels (similar to their depiction in the drama, 100 Days to Heaven). The protagonist's name is derived from the Philippine national personification.
Juan dela Cruz (Coco Martin) is the son of the mortal, Amelia (Mylene Dizon), and is the latest successor to a line of tagapagbantay. His mother died giving birth to him, leaving the child in the care of Father Cito (Jaime Fabregas), the town's curé. Unbeknownst to Juan, he also has aswang blood from his demon father, Samuel (Albert Martinez); should theaswang know of this fact, they will force him to join their ranks.
To suppress his demonic ancestry, Father Cito raises him to do good deeds and believe in God. However, the Bakal na Krus ("Cross of Steel") that his mother left before her death is stolen. The cross has the ability to shift into different weapons: a whip, a spear, a bow-and-arrow, and a sword, all with the power to vanquish evil. In his quest to find the missing Cross, he meets and falls in love with Rosario (Erich Gonzales), an undercover aswang-hunter.
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