After running unsuccessfully for the position of Governor of Indiana, Kern was selected as the vice presidential nominee at the 1908 Democratic National Convention.

Kern won election to the United States Senate in 1910, becoming a progressive ally of President Woodrow Wilson.

He also introduced the Kern Resolution, which led to the investigation of conditions in coal mines, and supported passage of the Seventeenth Amendment.

After these defeats, he returned to his law practice, traveled to Europe, and spent six months at a sanatorium in Asheville, North Carolina, for reasons of health.

His friendship with Bryan, as well as the fact that he was from the electorally important region of the Midwest, helped secure his place on the ticket, even over his objection.

Kern then sought election to the United States Senate from Indiana (the legislature then being Democratic-controlled), but was outmaneuvered by fellow Democrat Benjamin F. Shively.

In 1912, he helped write the Democratic platform, which had progressive planks in favor of banking and tariff reform and direct popular election of senators.

Kern's national stature as a progressive, his skill at conciliation, and his personal popularity resulted in his unanimous election as Chairman of the Democratic Caucus and de facto majority leader.

The resolution led to the Senate Committee on Education and Labor investigation into conditions in West Virginia coal mines.

He was originally interred at his summer home near Hollins, Virginia, and re-interred in Crown Hill Cemetery in Indianapolis twelve years later.