Origin of "A pox/curse on both their houses"

Pox is an alternate spelling of pocks, which has come to us directly from Old English. Pocks are the pustules of some diseases, notably small pox and syphilis, and the word became attached as the name of the disease as well. The OED finds a usage from 1530 in which the pocks is called a punishment from God, so to call down a pox on a house is to wish the punishing calamity of a deadly disease on the family.

"A Pox" upon you! Pox and intangible conduit. Applied in incantation to provide the means and assistance to the effectiveness of the incantation.

You have the correct play, Romeo and Juliet, but it's not from the end, but from Act 3 Scene 1. Mercutio (a Montague) says these words after being slain by Tybalt (a Capulet):

I am hurt.

A plague o' both your houses! I am sped.

The "houses" in this context are the two families, the Montagues and Capulets.