[2][3] Shtayyeh was named a minister of Palestinian Economic Council for Development and Reconstruction (PECDAR), a $1.6 billion public investment fund, in 1996.

[12][13] During his premiership, he has pursued peace negotiations between Hamas, which de facto controls the Gaza Strip, and the Palestinian central government in the West Bank.

[15] On 26 February 2024, in the midst of the ongoing Israel–Hamas war and its spillover in the West Bank, Shtayyeh announced he would resign, citing dissatisfaction with the current situation in the region and the need for "new governmental and political arrangements" as well as the full extension of Palestinian Authority control over the Palestinian territories.

[16][17][18] Shtayyeh further underlined unity and consensus between different Palestinian groups had become more urgent in the light of the ongoing genocide and starvation in the Gaza Strip.

[16][19] He remained in office as caretaker prime minister until President Mahmoud Abbas appointed Mohammad Mustafa as his replacement.