Santos was born in Buenos Aires, Argentina, in March, 1901, the youngest of five brothers. Santos' father, having completed a solid musical training at the Royal Conservatory of Naples, arrived in Buenos Aires from Italy. Although he had to settle with conducting the police and fireman brass bands to make a living, he was still able to found a small music academy which he managed until his death in 1906.

At the age of five, Enrique lost his dad. Four years later, his mother died. His childhood would be tainted by the grief of these deaths. At an early age, he learned to deal with the solitude of his loss by taking long walks alone, pacing the streets of the city, and seeking things and people to observe. He kept these habits for the rest of his life. Having been robbed of the warmth and comfort of family life, he chose to join "the humble community of the conventillo" and bare "his oxidized symphony of canned food."

He attended teaching school a few months but quickly abandoned this project to try his luck as a comedian. While playing in theatres from 1918 to 1925, he wrote a few playlets and melodies that, at the time, went unnoticed . He gained the reputation of being a dark and troubled man through his straight-forward style, and narration through uneasy often desperate characters. Indeed, his poetry can easily be labelled as nihilistic. Yet it is lively and full of surprising contrasts, often marked with humor.

Between 1925 and 1944, Discepolo wrote both the music and lyrics for over thirty tangos, some of which have become the most significant in the history of the tango.

In the remaining years of his life, Enrique wrote less. In 1951, he produced a series of very incisive radio broadcasts in which he spoke favourably of the social progress brought about by the Peron goverment. These political views made him a target for the opposition who then buried him in slander. He never fully recovered from these accusations nor from the lack of understanding shown by his fellow citizens. For him, his political views were in tune with his philosophy of social justice uttered in his tangos.

Enrique died of tubercolosis and sorrow on December 23rd 1951. In the words of poet and historian Horacio Salas : "after bearing the scars of others for so long, he had not enough strength to close up his own wounds."

When asked to comment on the his tangos, Discepolo answered: "at the beginning, there is always the street, that's why I walk through the city, trying to penetrate its essence, to feel, grasp its soul, deep down inside imagining, guessing what each passing man or woman would like to hear or sing at a happy or a sad time of their life. In my tangos, the main character is Buenos Aires. Sensibility and observation are all that is needed for the writing of my tango lyrics. " And Enrique had lots of sensibility. He was like a sponge, taking in the liveliness of all the living things around him. He had the power to transpose the grief of lost love as well as the troubles of his times within his tangos. His first successful tango, for which he wrote both music and lyrics, was named " Esta noche ne emborracho". Without any doubt, he was the most influential lyricist of what the historians term the "infamous years", which date from 1933 to 1943. During this period of economic and moral crisis, the tango stood still. Its roots seemed dryed out. Intellectuals and artists alike were prey to despair. Couragiously though, bearing the sarcastic remarks, defying censorship, Discepolo took a stand becoming a serial writer, a witness and a critic of his times.