Mikkelsen was born in Parlier, California and was raised in the Danish-American community of Askov, Minnesota. His father, Michael, was an immigrant from Denmark who became a Lutheran pastor in Askov.
Mikkelsen entered Hamline University in Saint Paul, Minnesota on a basketball scholarship at the age of 16. In his senior year, Mikkelsen led NCAA Division II in field goal percentage. Hamline won the 1949 NAIA Division I Men's Basketball Tournament and Mikkelsen was voted an All-American. He would later receive a master's degree in psychology from the University of Minnesota.
Mikkelsen played with George Mikan and Jim Pollard in the frontcourt of the Minneapolis Lakers. The Lakers won four NBA titles during Mikkelsen's career. Mikkelsen played in six NBA All-Star Games and was named to the All-NBA Second Team four times in his career.
Mikkelsen ended his career after ten seasons in the NBA in 1959, having played in 699 of a possible 704 regular season games. He led the NBA in both personal fouls and disqualifications for three straight seasons during his career, and finished his career with 10,063 points scored. Mikkelsen still holds the league record for career disqualifications with 127, which he did in only 631 games — disqualifications were not recorded in the NBA until his second season.
In 1956, Mikkelsen was inducted into the NAIA Basketball Hall of Fame.
Mikkelsen was inducted into the Naismith Memorial Basketball Hall of Fame in 1995 along with Laker coach John Kundla.
In 2002, during halftime of a Lakers/Timberwolves game, Mikkelsen and fellow Hall of Fame teammates George Mikan, Slater Martin, Arlee Pollard (widow of Jim Pollard), Clyde Lovellette and Coach John Kundla were each presented with championship rings. The Minneapolis players received the same rings provided by the NBA to the champion Los Angeles Lakers that same year.
Mikkelsen later coached and was general manager of the Minnesota Pipers of the American Basketball Association.
Mikkelsen's wife Jean died in 2002 after 47 years of marriage. Their two sons are named Tom and John. In 2006 a biography was published by John Egan titled The Vern Mikkelsen Story.
Mikkelsen died on November 21, 2013 in Wayzata, Minnesota surrounded by his family.