Born in Chattanooga, Ohio, a small town in Mercer County on the Indiana border, Betzel played his entire, five-year Major League career for the St. Louis Cardinals, between 1914 and 1918.

An old-time ballplayer who roomed with Rogers Hornsby in his tenure with the Cardinals, Betzel once beaned Ty Cobb with an infield ground ball that set off a rare brawl in spring training.

In 1927 Bruno began his managing career with the Indianapolis Indians of the Class AA American Association; the following season, he won his first pennant.

After farm systems were adopted in the 1930s, Betzel piloted minor league affiliates of the Yankees, Brooklyn Dodgers, New York Giants and Cincinnati Reds.

According to Official Baseball 1945, Betzel was endowed with six given names to honor all six of his uncles; he gained his lifelong nickname "Bruno" after a St. Bernard Dog of his youth that used to follow him around.