When he attended the Imperial Academy of Arts in 1852–58, his Romantic treatment of patriotic themes won him the admiration of the Russian royalty and he was asked to teach drawing to the Grand Duchesses.

Although his forte was battle painting, Mikeshin's sketch won the much-publicized contest for the monument to the Millennium of Russia in 1859.

He illustrated the official motto Orthodoxy, Autocracy, and Nationality in designs for bombastic outdoor statues of Kuzma Minin in Nizhny Novgorod, Admiral Greig in Nikolayev, and Alexander II of Russia in Rostov-on-Don.

The Khmelnytsky monument was at the center of controversy, as the original version would have depicted the 17th-century Cossack leader trampling a Pole, a Jew, and a Catholic priest under the hooves of the horse.

In 1876–1878, Mikeshin was the editor of Pchela [ru], a satirical magazine in which he published his caricatures and illustrations to the works of Nikolai Gogol and Taras Shevchenko.