Born in Cumberland County, New Jersey, Henderson worked as a flatboatman on the Mississippi River and studied law.

In 1838, Henderson was elected a Whig to the United States Senate, serving one full term, 1839 to 1845.

In 1851, he was tried in the United States District Court in New Orleans for violation of the neutrality laws of 1817 for complicity in expeditions conducted by Venezuelan filibuster Narciso Lopez to liberate Cuba from Spanish rule, however was acquitted.

A further attempt at filibustering ended in disaster when Lopez's 1851 invasion force was captured and many of them executed.

Henderson retired from public life and died in Pass Christian, Mississippi on September 15, 1857.