[6] Ousmane won the election, defeating Tandja Mamadou, the candidate of the National Movement of the Development Society (MNSD); with the AFC holding a parliamentary majority, Issoufou became Prime Minister on 17 April 1993.

On 28 September 1994, Issoufou resigned in response to a decree from Ousmane a week earlier that weakened the powers of the prime minister, and the PNDS withdrew from the governing coalition.

The opposition's victory in the election led to cohabitation between President Ousmane and a government, backed by a parliamentary majority, that opposed him; the result was political deadlock.

[6] Issoufou placed fourth (receiving only 7.60% of the vote) in the flawed and controversial 7–8 July 1996 presidential election that gave Maïnassara an outright victory.

[7] Afterward, he refused to meet with Maïnassara, unsuccessfully appealed to the Supreme Court for the election to be annulled, and the PNDS called for demonstrations.

[8] On 26 July he was again placed under house arrest, along with another leading PNDS member, Mohamed Bazoum; they were freed on the order of a judge on 12 August.

At an opposition rally in Niamey on 9 May 2009, Issoufou accused Tandja of seeking "a new constitution to stay in power forever" and the establishment of "a dictatorship and a monarchy".

Accusing Tandja of undertaking a coup d'état, "violating the constitution and ... forfeit[ing] all political and moral legitimacy", Issoufou called on the armed forces to ignore his orders and urged the international community to intervene.

Speaking on 8 August, shortly after the announcement of results, Issoufou vowed that the opposition would "resist and fight against this coup d'etat enacted by President Tandja and against his aim of installing a dictatorship in our country".

[21] Tandja was ousted in a February 2010 military coup, and a new transitional junta enabled the opposition leaders to return to politics in Niger while preparing for elections in 2011.

[22] Issoufou won the January–March 2011 presidential election in a second round of voting against MNSD candidate Seyni Oumarou and was inaugurated as president on 7 April 2011, succeeding Salou Djibo, the Chairman of the Supreme Council for the Restoration of Democracy.

[27] On 31 March 2021, two days before Issoufou's term was to expire, his government thwarted a coup attempt by dissident military officers believed to have been plotting to prevent the inauguration of his successor, Mohamed Bazoum.

[28] Following Bazoum's removal and detention during the 2023 Nigerien coup d'état in July, Issoufou was reportedly involved in negotiations for his release.

[30] His son, Bazoum's oil minister Mahamane Sani Mahamadou was among several officials arrested by the military junta formed after the coup.