The construction of the new church began in 1877 on the site of the old Panteleimon Church, which was built in 1871 near the hospital cemetery in Tashkent. The funding for the construction was provided by donations from the townspeople. Among them was the Turkestan Governor-General K. P. von Kaufman, who donated 3000 rubles. The largest contribution came from Tashkent merchant of the first guild Dmitry Zakho, who then served as the church elder for 15 years.

The construction was completed in 1878, and on January 31, 1879, the church was consecrated in honor of the great martyr and healer Panteleimon.

In 1922, the parish, like many others in Central Asia, came under the administration of the Renovationist Synod of the Orthodox Russian Church. In 1933, the church was closed for services, and until 1945, its building housed a sanitary warehouse of the Central Asian Military District. In December 1945, the church was returned to the faithful and re-consecrated in honor of the Assumption of the Blessed Virgin Mary, receiving the status of the cathedral of the Tashkent Diocese. In 1958 and 1960, under Bishop Yermogen (Golubev), the building was reconstructed and significantly expanded.

In the early 1990s, the bell tower and domes of the cathedral were renovated, the adjacent territory was expanded and improved, and the interior decoration became more lavish. On November 10, 1996, Patriarch of Moscow and all Rus Alexy II held a service in the cathedral during his visit to Tashkent.

In 2014, a decision was made to build an additional church of Luke in the cathedral for conducting funerals.