Despite being Isaacs' only novel, María is considered one of the most important works of 19th century Spanish American literature. The novel has been compared to Chateaubriand's, but the mournful and ominous tone of the narrative echoes the style of Edgar Allan Poe. Notable are the description of the landscape and the artistic style of the prose.
The novel has several autobiographical elements, such as both main characters being natives of Valle del Cauca, or Efraín's departure to Bogotá to pursue his studies. It has been claimed that Maria herself is based, at least in part, upon a cousin of the author. The hacienda "El Paraíso", owned by Isaacs' family, also figures as an important location throughout the novel; it is currently preserved as a museum.
The story relates the tragic love story between María and her cousin Efraín, both natives of Valle del Cauca. The characters fall in love with each other but circumstances prevent the full realization of their love. The first hurdle is Efraín's departure for six years to Bogotá in order to pursue his studies. After Efraín returns to Cauca the couple is able to live together, albeit for only three months, before he leaves for London to continue his education. Two years later Efraín returns to Colombia to find that María has died of illness. Heart-broken, Efraín decides to leave Cauca definitely, this time without a fixed destination.