In the early 16th century Portuguese merchants came to Arabia and took over the Red Sea trade routes between Egypt and India. The Portuguese annexed the island of Socotra in the Indian Ocean, and from that vantage point tried unsuccessfully to take control of Aden. Following the Portuguese, the Egyptian Mamelukes attempted to take power in Yemen, successfully capturing Sanaa but failing to take Aden. Armies of the Ottoman Empire conquered Egypt in 1517, and in 1538 brought most of Yemen under their control. The Ottomans were expelled nearly a century later, after a long struggle led by the Zaydi imamate that united and strengthened Yemeni identity and ushered in a long period of Zaydi rule.

Yemen developed an extensive coffee trade under Ottoman rule, with the coastal town of Mocha (Al Mukha) becoming a coffee port of international importance; despite this, the highlands of Yemen remained economically and culturally isolated from the outside world from the mid-17th century to nearly the mid-19th century, a period during which Western Europe was greatly influenced by modern thought and technology.

The process by which Yemen and the Yemeni people were divided into two countries began with the British seizure of Aden in 1839 and the reoccupation of North Yemen by the Ottomans in 1849. Throughout the second half of the 19th century, both the Ottomans and the British expanded their control of Yemeni lands. In the early 20th century, the two powers drew a border between their territories, which came to be called North and South Yemen, respectively. This boundary remained intact for most of the 20th century.

In North Yemen, Ottoman rule met with significant opposition during the early 1900s. Under the leadership of the Zaydi imam, Yemenis staged many uprisings. After years of rebellion, in 1911 the Ottomans finally granted the imam autonomy over much of North Yemen. Defeat in World War I forced the Ottomans to evacuate Yemen in 1918.