The offer of the throne of Spain to his eldest son, Leopold, was one of the causes of the Franco-Prussian War, which led to the unification of Germany and the creation of the German Empire.

Within the principality, the revolutionary movement became increasingly radicalized, leading to a dispute with the estates over the princely domains that forced Karl Anton to temporarily leave Hohenzollern-Sigmaringen.

On 3 June a people's assembly was held calling for the unification of the military and the citizen army, the free election of officers, and the transfer of the princely domains to the state.

Beginning in the spring of 1848, Karl Anton conducted secret negotiations with Frederick William IV on the annexation of the principality to the Kingdom of Prussia.

[2] On 7 December 1849, Prince Karl Anton signed the state treaty with Prussia,[1] and the solemn handover of the principality took place on 6 April 1850.

After Wilhelm assumed the regency on 5 November 1858, he entrusted Karl Anton with office of Minister President of Prussia and asked him to submit his proposal for building a ministry.

[1] Politically Karl Anton was close to the moderate liberalism of the Wochenblatt Party, an association of Prussian liberal-conservative politicians led by August von Bethmann-Hollweg.

After leaving the Prussian government, Karl Anton largely resigned from active politics and focused on his role as head of the Catholic branch of the Hohenzollern family, a position that was accentuated by the extinction of the Hohenzollern-Hechingen line in 1869.

When the candidacy threatened to ignite a European crisis, Karl Anton withdrew his son's name on 12 July 1870, but it was not enough to prevent the Franco-Prussian War of 1870/71.