From 2005 to 2008, she was the press secretary of the Permanent Mission of the Russian Federation to the United Nations in New York City.

From 2011 to 10 August 2015, Zakharova was the Deputy Head of the Department of Information and Press of the Ministry of Foreign Affairs of the Russian Federation.

[5] On 10 August 2015, by order of the Ministry of Foreign Affairs, Zakharova was appointed director of the Information and Press Department.

[8] In 2017, Zakharova accused the European Union of hypocrisy over its different behaviour towards the separatist crises in Crimea and Catalonia, after hundreds were injured by Spanish security forces preventing Catalans from voting during the Catalan independence referendum, saying "I see and read what is happening in Catalonia.

When Couric brought up the reports of torture against LGBT individuals by the Chechen government, Zakharova said that Russia was conducting an investigation into the matter.

She also said that China was a "like-minded partner" and Russia had developed ties with many countries in Asia, Africa, the Middle East and Latin America.

[27] On 10 August 2024, she condemned the Al-Tabaeen school attack in Gaza, stating that it undermine international efforts to de-escalate the Israel–Hamas war and reach an urgent ceasefire and prisoner-captive exchange.

[28] On 11 August 2024, Zakharova protested against the Ukrainian incursion into the Kursk Oblast, stating that Ukraine "is continuing its terrorist activity with the sole purpose of intimidating the peaceful population of Russia" and that the incursion "makes no sense from a military point of view.

"[29] On 17 August 2024, The Washington Post reported, citing anonymous diplomatic sources, that Ukraine's incursion into Russia disrupted plans for indirect talks in Qatar to halt mutual strikes on energy infrastructure in Ukraine and Russia.

[30] Zakharova said that there were "no direct or indirect negotiations between Russia and Ukraine on the safety of civilian critical infrastructure facilities" and that after the assault on the Kursk Oblast, Putin ruled out the possibility of such talks.

[31] On 20 August 2024, she condemned the Verkhovna Rada's vote to ban the Ukrainian Orthodox Church of the Moscow Patriarchate (UOC-MP), accusing Ukraine of trying to "destroy true Orthodoxy.

"[32] On 23 February 2022, a day before Russia invaded Ukraine, she was sanctioned by the European Union alongside other prominent Russian media figures, as "a central figure of the government propaganda," and for having "promoted the deployment of Russian forces in Ukraine."