After two years, a news spread among the Muslims in Abyssinia that the Quraish of Makkah had accepted Islam. That made Uthman, Ruqayya, and some other Muslims return to Makkah. When these Muslims reached Makkah it transpired that the news about the Quraish having accepted Islam was false. Some of the Muslims who had come from Abyssinia returned there, but Uthman and Ruqayya decided to stay in Makkah.

In Makkah, Uthman had to start his business afresh. The contacts that he had established in Abyssinia stood in good stead and the business of Uthman prospered. Although the number of the Muslims steadily grew, there was no relaxation in the persecution of the Muslims by the Quraish. The family of Uthman continued their pressure, but Uthman's faith in Islam was too firm to know of any wavering. In the persecution of the Muslims, Uqba b Abi Muheet, the step-father of Uthman (the man his mother had married) was in the forefront. One day Uqba put his sheet round the neck of the Holy Prophet, while he was praying in the Kaaba, and tried to strangle him. Abu Bakr and Uthman rushed to the aid of the Holy Prophet, and frustrated the evil design of Uqba.

In Makkah, Uthman spent most of his time in the company of the Holy Prophet. He liberally helped such Muslims who were poor. He liberated some Muslim slaves.

When the Holy Prophet and the members of the Banu Hashim were shut up in the valley outside Makkah as a consequence of social boycott by the Quraish, Uthman took steps to ensure that there was no break in the supply of provisions to the besieged persons. Uthman exercised his influence on the youth among the Quraish to create an opinion in favor of the lifting of the boycott.

When after the lifting of the boycott, the Holy Prophet had his experience of the "Miraj" (ascension), there were some persons who were skeptical about it. Abu Bakr and Uthman, however, believed in letter as well as in spirit what the Holy Prophet said.

When in 622 C.E., the Holy Prophet advised the Muslims to migrate to Yathrib, Uthman migrated to Yathrib with his wife Ruqayya. Uthman was among the few Muslims who undertook two migrations in the cause of Allah, once to Abyssinia and for the second time to Yathrib