Hydromorphone is used in medicine as an alternative to morphine for analgesia, and as a second- or third-line narcotic antitussive (cough suppressant) for cases of dry, painful, paroxysmal coughing resulting from continuing bronchial irritation after influenza and other ailments, inhalation of fungus, and other causes. In general, it is considered the strongest of the antitussive drugs, and was developed shortly after diacetylmorphine (heroin) was removed from clinical use for this purpose in most of the world and banned outright in many countries. The effectiveness of hydrocodone as an antitussive may be partly due to it being partially converted to hydromorphone in the liver.

Hydromorphone should not be confused with hydromorphinol, also known as 14-hydroxydihydromorphine and RAM-320, or dihydromorphine (Paramorfan). While all of these are strong opioids, they are indeed different drugs. Additional confusion arises from the fact that, in a handful of countries, hydromorphinol is distributed under the brand name Numorphan, which is the marketed name for oxymorphone in the rest of the world, according to the current version of The A-Z Encyclopaedia of Alcohol & Drug Abuse and other references.

Hydromorphone is used to relieve moderate to severe pain and severe, painful dry coughing. Hydromorphone is becoming more popular in the treatment of chronic pain in many countries, including the United States.^{[citation needed]} Hydromorphone displays superior solubility and speed of onset, a less troublesome side effect profile, and lower dependence liability as compared to morphine and diamorphine. It is thought to be 6-8 times stronger than morphine^{[citation needed]}, but with a lower risk of dependency. Hydromorphone is, therefore, preferred over morphine in many areas ranging from the ongoing treatment of chronic pain syndromes, the emergency department to the operating suite.^{[citation needed]} Hydromorphone lacks the toxic metabolites (e.g., norpethidine) of many opioids related to pethidine and some of the methadone and tends to cause less nausea than morphine. It is a common alternative for those tending to have hallucinations from fentanyl administered through dermal patches and other dosage forms.^{[citation needed]}

In addition to the above, hydromorphone usually proves to be the best alternative of choice to morphine and fentanyl in severe chronic pain, especially for severe breakthrough pain.