Khadija was a very successful merchant. It is said that when the Quraysh’s trade caravan travellers gathered to embark upon their summer journey to Syria or winter journey to Yemen, Khadija’s caravan equaled the caravans of all other traders of the Quraysh put together. Khadija was given many honorifics, including "The Pious One", "Princess of Quraysh" (Ameerat-Quraysh), and "Khadija the Great" (Khadija al-Kubra). It is said that she fed and clothed the poor, assisted her relatives financially, and provided marriage portions for poor relations. Khadija was said to have neither believed in nor worshipped idols, which was atypical for pre-Islamic Arabian culture.

Khadija did not travel with her trade caravans; instead, she employed others to trade on her behalf for a commission. In 595 Khadija needed a co-worker for a transaction in Syria. She hired Muhammad ibn Abdullah, then 25 years old, for the trade in Syria, sending word that she would pay to double her usual commission. With the permission of Abu Talib ibn Muttalib, his uncle, Muhammad was sent to Syria with one of Khadija’s servants. This caravan experience earned Muhammad the honorifics of al-Sadiq (the Truthful) and al-Amin ("the Trustworthy" or "the Honest").

She sent one of her servants, Maysarah, to assist him. Upon returning, Maysarah gave accounts of the honourable way in which Muhammad had conducted his business, bringing back twice as much profit as Khadija had expected.