After his collegiate football career, Wilke started as a stuntman in the 1930s and his first appearance on screen was in San Francisco (1936). He soon began to acquire regular character parts, mainly as a heavy, and made his mark when, along with Lee Van Cleef and Sheb Wooley, he played one of the "three men waiting at the station" in High Noon (1952).

He appeared eight times from 1951-1953 on the syndicated western series The Range Rider, starring Jock Mahoney and Dick Jones. He was a guest star five times thereafter on Cheyenne, five times on Bonanza, four times on Wagon Train and Death Valley Days, and three times on Clint Eastwood's Rawhide, Duncan Renaldo's The Cisco Kid, Pat Conway's Tombstone Territory, and Fess Parker's Daniel Boone. He appeared twice on The Virginian, Cimarron Strip, and The Guns of Will Sonnett, and once on Barry Sullivan's The Tall Man, Kirby Grant's Sky King, Andrew Duggan's Lancer, Robert Conrad's The Wild Wild West, and the ABC family western The Monroes.

His drama/adventure roles included U.S. Marshal, Peter Gunn, Tarzan, Bourbon Street Beat, 77 Sunset Strip, and The Untouchables. In 1953 Wilke, playing a henchman for an East European counterfeiter, shoved John Hamilton and George Reeves into side-by-side steam cabinets, locked them in, turned up the thermostat to charbroil and left them to bake in "Perry White's Scoop", an episode of the popular series Adventures of Superman.

Wilke played a hitman in The Far Country (1954) and continued to work steadily in films and television over the next 20 years. More western credits followed in Man of the West (1958) and numerous lesser-known films.

Wilke appeared as a dishonest fight promoter in the 1958 episode "The Fighter" of NBC's western series, Bat Masterson, having engaged on screen in fisticuffs with Gene Barry, who played Masterson.

In 1960 Wilke had a small but memorable part in The Magnificent Seven as the railroad bully, Wallace, who was quickly killed off by James Coburn in the memorable gun vs. knife fight. He had an unusually sympathetic (and large) role in Days of Heaven (1978) as farmer Sam Shepard's ally, the farm foreman.

In 1961 Wilke appeared as Gil Fletcher, a corrupt marshal in Billings, Montana, in the episode "The Fatal Step" of NBC's Laramie. Fletcher tries to steal the $20,000 payroll taken in a stage robbery by Wes Darrin (played by Dennis Patrick) and a younger partner, Tad Kimball (Gary Clarke, later a regular on The Virginian). Series character Jess Harper, played by Robert Fuller, is riding shotgun on the stage. Kimball regrets taking part in the crime and tries belatedly to make amends, as Fletcher tries to seize the loot stashed in an abandoned mine by Darrin and Kimball. Series character Slim Sherman, played by John Smith, shoots Fletcher in self-defense and remarks that he had never before drawn on a lawman and hoped never again to shoot at a badge.

Wilke played Deputy Sheriff Connors in the 1963 episode, "The Case of the Drowsy Mosquito" on CBS' Perry Mason. He demonstrated his versatility by portraying golf professional Danny Donnigan in a 1962 episode, "Robbie the Caddie", on Fred MacMurray's ABC sitcom, My Three Sons (in real life Wilke was an expert Golfer, and his friend actor Claude Akins noted that Wilke made more money on the golf course than he ever did as an actor). In 1964 Wilke played Tom Carter, the golf instructor of Lucy Carmichael (Lucille Ball), in The Lucy Show episode "Lucy Takes Up Golf".

In the 1965-66 television season Wilke played a lawman, Marshal Sam Corbett, in the 34-episode ABC western series The Legend of Jesse James, who (in vain) tried to capture the outlaws Jesse James and his brother Frank James. Ann Doran co-starred as the James boys' mother Zerelda James Samuel. In 1960 Wilke played Jesse James' associate Cole Younger in the short-lived NBC western series Overland Trail with william Bendix and Doug McClure. In his only appearance on Perry Mason, Wilke played Deputy Sheriff Connors in the 1963 episode "The Case of the Drowsy Mosquito."

In 1966 Wilke was cast as the courageous Sheriff McBain in the episode "Brute Angel" of the syndicated western series Death Valley Days, hosted by Robert Taylor. In the story line McBain must arrest young cutthroat Sam Bolt (Sherwood Price) and transport him stand trial for murder in Denver. McBain prays for Divine intervention; his friend Pony Cragin (Jim Davis) hears the prayer and removes bullets from Bolt's gun prior to the arrest attempt. Jean Engstrom is cast as McBain's wife, Esther.

Wilke's final film role was somewhat against type as Gen. Barnicke in the 1981 comedy Stripes.

Wilke guest-starred on many other television westerns, including Maverick, Tales of Wells Fargo, Have Gun – Will Travel, Bronco, The Westerner, Cheyenne, Lawman, Wanted Dead or Alive, Zorro, The Rifleman, and The Untouchables 1962 episode "The Eddie O'Gara Story" playing vicious gangster George "Bugs" Moran.