After being ordained to the Reformed Church ministry by the Pella, Iowa Classis in 1890, he was a missionary at Busrah, Bahrein, and at other locations in Arabia from 1891 to 1905.

Zwemer retired from active work on the faculty of Princeton College Seminary at the age of seventy, but continued to write and publish books and articles as well as doing a great deal of public speaking.

According to Ruth A. Tucker, PhD, Samuel Zwemer's converts were "probably less than a dozen during his nearly forty years of service" but his "greatest contribution to missions was that of stirring Christians to the need for evangelism among Muslims".

[10] In the tradition of Lull,[11] Zwemer 'left behind a mighty highway of print almost a book a year in English for over half a century.

'[12] As part of this great literary undertaking, he settled in Cairo in 1912 to work with the Nile Mission Press to make it 'a production point for Christian Literature for Muslims.

'[18] Zwemer's third milestone was accepting a professorship at Princeton in 1929 and marked an era of equipping and recruiting for the missionary movement, though this had been a significant aspect of his career from the beginning.

In an extended period of furlough he was a traveling representative for the Student Volunteer Movement, and his speaking ability in motivating for missions was legendary.

[21] J. Christy Wilson Jr. summarizes: 'Speer and Zwemer probably influenced more young men and women to go into missionary service than any two individuals in all of Christian history.

'[20] As a result of his direct pioneering work, four mission stations had been set up, and though only small in number,[22] 'the converts showed unusual courage in professing their faith.

[28] He praised the all encompassing idea of God in Islam, seeing it as the 'Calvinism of the Orient,'[29] and even placed the Bismillah on his study wall in Cairo[30] and on the cover of his journal "The Moslem World".

'[40] He sees this grand vision as coming directly from Calvin: 'God has created the entire world that it should be the theater of his glory by the spread of his Gospel.

'[41] It was this unshakable belief in the infinite power and supremacy of God that drove Zwemer to the 'cradle of Islam' as a demonstration of the 'Glory of the Impossible'.

[45] Lyle Vander Werff describes Zwemer's missiological approach as 'Christocentric-anthropological', that is, the Gospel message is the greatest need of the Muslim as opposed to Western Civilization or 'philanthropic programs of education'.

[51] His opening editorial for The Moslem World stated that it aimed 'to represent no faction or fraction of the Church, but to be broad in the best sense of the word.

[54] Such desire for ecumenism was fed by his all-pervasive passion for mission to Islam: 'the issues at stake are too vital and the urgency too great for anything but united front.