Wang was born in the foreign legation quarter of Beijing in 1900 while it was under siege of the Boxers. His early life was one of extreme poverty and repeated illness; but he had an inquiring mind and did well at a London Missionary Society school. He later said his poverty had been something of a spiritual advantage because there were many sins that took money to commit. At first Wang hoped to become a great political leader, and he put a picture of Abraham Lincoln on his wall to remind himself of his goal.

Converted to Christianity at fourteen, Wang came to believe "that all kinds of sinful practices in society had their exact counterparts in the church." He decided that the church "needed a revolution" and that God had entrusted to him the mission of bringing it about. In 1919 Wang became a Teacher at a Presbyterian mission school in Baoding, a hundred miles south of the capital, but was dismissed in 1920 when he insisted on being baptized by immersion. His mother and sister thought his behavior so peculiar that they believed him mentally ill, and Wang himself later admitted that the "persecution" he had received from others was in part the result of his own immaturity.

Wang's personal name was "Yong-shung" (Chinese: 永盛; pinyin: Yǒngshèng) until 1920, when he "unconditionally submitted to God" and formally changed his name to "Mingdao" (Chinese: 明道; pinyin: Míngdào) which means approximately "Testify to the Way."

In 1923, after a good deal of personal Bible study but no formal theological training, Wang moved towards a more mature understanding of the Protestant doctrine of justification by faith. In February 1925, he began holding religious meetings in his home in Peking, meetings which eventuated in the founding of the Christian Tabernacle, a church which by 1937 had its own building seating several hundred, and which was one of the largest evangelical churches in China during the 1940s. Wang also had an itinerant ministry throughout China, visiting twenty-four of the twenty-eight provinces and taking the pulpit in churches of thirty different denominations. Wang was often absent from his own church for six months of the year. In 1926, Wang began publishing a religious newspaper, Spiritual Food Quarterly (Chinese: 靈食季刊; pinyin: Líng shí jìkān).

In 1928, Wang (through what might be called semi-arrangement) married Liu Jing Wen, the much younger daughter of a Protestant pastor in Hangzhou. They experienced a long and happy marriage and had a son, Wang Tianzhe, who survived them; but their temperaments were remarkably dissimilar. Wang was obsessive about details, whereas his wife was (in his words) "only concerned about the general effect," "happy-go-lucky," and "very forgetful." Wang could be hasty to the point of rashness, and he also frequently failed to express proper sympathy or sensitivity. Jing Wen was exceptionally patient and considerate of others, but she stunned Wang by correcting him in public, taking the view that since he had spoken unwisely in front of others, she had the duty to correct him before others as well. Wang recalled that after twenty years of instruction from his wife, he had made "a measure of progress," but he also warned readers of his autobiography that Jing Wen "should not necessarily be taken as a model in this respect." Wang's sermons also reflected changes in gender relations that occurred during the early Republican period, and he preached about marriage, concubinage, and the place of woman in the family.

In August 1955, Wang was arrested for refusing to join the Three-Self Patriotic Movement (TSPM), the state-controlled church. A few months earlier Wang had written a long article attacking the Three-Self Committee headed by Wu Yaozong as a group composed of modernist unbelievers with whom true Christians should have nothing to do. Wang, his wife, and eighteen church members, were imprisoned, and the Christian Tabernacle was closed. After signing a confession, making a humiliating plea for mercy from those he had previously denounced as "false Prophets," and promising to participate in the TSPM, Wang was released from prison. Then after recovering from a possible nervous breakdown, Wang recanted, was rearrested in 1957, and was sentenced to life imprisonment in 1963. After the United States reestablished diplomatic relations with China in 1972, human rights organizations began to pressure China to release its political prisoners. When the Chinese government attempted to release Wang in 1979, he refused (like St. Paul in Acts 16: 35-40) to leave until his name had been cleared. In 1980 the prison tricked Wang into leaving, in Wang's words "not released but...forced out by deception."

Between 1987 and 1989, Wang's physical and mental abilities noticeably declined. In July 1991, Wang was diagnosed with blood clots on his brain, and he died on July 28, followed by his wife's death in 1992. As one authority has noted, despite Wang's old age and declining influence, he had "remained an unrivaled symbol of uncompromising faith until his death."