Barrymore especializou-se na comédia ligeira até ser convencido por seu amigo, o escritor teatral [[Edward Sheldon]], a tentar dramas sérios. Depois disso, Barrymore causou sensação em "''Justice''" (1916), de [[John Galsworthy]], co-estrelada por [[Cathleen Nesbitt]]. Seria Cathleen Nesbitt quem o apresentaria a [[Blanche Oelrichs]]. A este triunfo seguiram-se diversos sucessos em palcos da [[Broadway]]: "''[[Peter Ibbetson]]''" (1917) (em papel que seu pai Maurice desejava interpretar), "''Redenção''" (1918) de [[Leon Tolstoi]] e "''The Jest''" (1919), co-estrelada por seu irmão [[Lionel Barrymore]], alcançando o que parece ter sido seu zenite na carreira teatral com "''[[Ricardo III (peça)|Ricardo III]]''", em 1920. Barrymore sofre um aparente fracasso em sua carreira teatral com a peça "''Clair de Lune''" (1921), escrita por sua mulher [[Michael Strange]], mas depois apresenta seu maior sucesso no teatro com "''[[Hamlet]]''" (1922), que interpreta na Broadway durante 101 apresentações, seguindo a seguir para [[Londres]], em 1925.
Barrymore entered films around 1913 with the feature ''An American Citizen''. He or someone using the name ''Jack Barrymore'' is given credit for four short films made in 1912 and 1913 but this has not been proven to be John Barrymore. Barrymore was most likely convinced into giving films a try out of economic necessity and the fact that he hated touring a play all over the United States. He could make a couple of movies in the off-season theater months or shoot a film in one part of a day while doing a play in another part. He also may have been goaded into films by his brother Lionel and his uncle Sidney, who had both been successfully making movies for a couple of years. Some of Barrymore's silent film roles included [[A. J. Raffles]] in ''[[Raffles The Amateur Cracksman (1917 film)|Raffles the Amateur Cracksman]]'' (1917), ''[[Dr. Jekyll and Mr. Hyde (1920 film)|Dr. Jekyll and Mr. Hyde]]'' (1920), ''[[Sherlock Holmes (1922 film)|Sherlock Holmes]]'' (1922), ''[[Beau Brummel (1924 film)|Beau Brummel]]'' (1924), [[Captain Ahab]] in ''[[The Sea Beast]]'' (1926), and ''[[Don Juan (film)|Don Juan]]'' (1926). When talking pictures arrived, Barrymore's stage-trained voice added a new dimension to his screen work. He made his talkie debut with a dramatic reading of the big Richard III speech from ''[[Henry VI, part 2]]'' in [[Warner Brothers]]' musical revue ''[[The Show of Shows (film)|'The Show of Shows]]'' (''"Would they were wasted: marrow, bones and all"'') , and reprised his Captain Ahab role in ''[[Moby Dick (1930 film)|Moby Dick]]'' (1930). His other leads included ''[[The Man from Blankley's]]'' (1930), ''[[Svengali (1931 film)|Svengali]]'' (1931), ''[[The Mad Genius]]'' (1931), ''[[Grand Hotel (film)|Grand Hotel]]'' (1932) (in which he displays an affectionate chemistry with his brother Lionel), ''[[Dinner at Eight (1933 film)|Dinner at Eight]]'' (1933), ''[[Topaze (1933 American film)|Topaze]]'' (1933) and ''[[Twentieth Century (movie)|Twentieth Century]]'' (1934). He worked opposite many of the screen's foremost leading ladies, including [[Greta Garbo]], [[Katharine Hepburn]], [[Jean Harlow]], [[Joan Crawford]], and [[Carole Lombard]]. In 1933, Barrymore appeared as a Jewish attorney in the title role of ''[[Counsellor at Law]]'' based on [[Elmer Rice]]'s 1931 play. As critic [[Pauline Kael]] later wrote, he "seems an unlikely choice for the ghetto-born lawyer...but this is one of the few screen roles that reveal his measure as an actor. His 'presence' is apparent in every scene; so are his restraint, his humor, and his zest."