Sandow, after a brief period of study with the legendary strongman Louis Durlacher (“Professor Attila”), first attracted attention by breaking strength-testing machines in the cafés of Amsterdam. But his reputation was established in a series of challenge matches against the leading strongmen of the 1880s, including Charles Sampson, Frank (“Cyclops”) Bienkowski, and Henry (“Hercules”) McCann. His match with McCann in 1890 served as a model for later strongman competitions.

As a showman, Sandow broke cables and chains, lifted people, and performed a variety of strongman movements. He also displayed his well-developed physique to enthusiastic audiences in England and the United States. At the 1893 World's Columbian Exposition in Chicago he joined Florenz Ziegfeld (Ziegfeld, Florenz, Jr.)'s Trocadero Company and toured the continent for several years. Ziegfeld's Follies and his glorification of the American girl were inspired in part by his earlier successful showcasing of Sandow. Noted physical educator Dudley Sargent of Harvard University examined Sandow and judged him to be the finest specimen of manhood he had seen. By the time he left America, Sandow's name was a household word, and he had earned more than a quarter million dollars.

Upon returning to London, Sandow promoted various fitness enterprises, the most important being his Institute of physical culture, which opened in 1897 and led to numerous other centres throughout Great Britain. Sandow also capitalized on his fame by marketing various physical culture publications, exercise devices, and dietary products. Catering to a heightened Victorian fascination with the human body, he staged a precedent-setting physique (bodybuilding) contest for an overflow audience in 1901 in London's Albert Hall. One of the judges was the writer Arthur Conan Doyle (Conan Doyle, Sir Arthur). Sandow later promoted his health-and-fitness gospel on an extensive world tour and influenced such prominent physical culturists as Theodore Roosevelt (Roosevelt, Theodore). His greatest honour came in 1911 when he was appointed Professor of Scientific and Physical Culture to King George V of the United Kingdom.

In later life Sandow founded his Curative Institute of Physical Culture, an urban sanatorium that treated neurasthenia, an affliction that was prevalent among the middle and upper classes. In 1919 he addressed the more general needs of military readiness and national survival arising from World War I in Life Is Movement, his most important book.