Wayne Franklin began his professional baseball career after being drafted by the Los Angeles Dodgers in the 36th round of the 1996 amateur draft. The left-hander joined the Los Angeles farm team the Yakima Bears in 1996, where he went 1-0 with one save and a 2.52 ERA. The following year, he pitched mostly as a reliever for the Single-A Savannah Sand Gnats. He did, however, make seven starts, and he finished the 1997 season with a 5-3 record, a 3.11 ERA, and two saves. In 1998, playing with the Vero Beach Dodgers, Franklin earned a career-high nine wins and also notched ten saves and a 3.53 ERA in 86.2 innings pitched. Between the 1998 and 1999 seasons, Franklin was drafted by the Houston Astros in the Rule 5 Draft. Wayne posted a 3-0 record with a 1.53 ERA in 12 games for Single-A Kissimmee, prompting a promotion to the Jackson Generals in May 1999. After being called up, Franklin recorded a 3-1 record with 20 saves and a 1.61 ERA and was named to the Texas League All-Star team, placing second in relievers with a .178 opponent batting average.

Franklin began the 2000 season with the AAA New Orleans Zephyrs, but was called up to the Astros after forty-eight games when he put up a 3-3 record with a 3.63 ERA. He made his big league debut with the Astros on July 24 against the Cincinnati Reds. Interesting to note is that Ken Griffey Jr. was the first out Wayne recorded in the major leagues. Wayne proceeded to record a 2.79 ERA in 16 appearances and only gave up 6 hits to 34 batters faced. In 2001, Wayne was on the Houston Opening Day roster and made eleven relief outings, but was sent down to the Zephyrs in May after putting up a 6.75 earned run average. With New Orleans, he went 2-1 with 51 strikeouts in 41 relief appearances. In 2002, Franklin became a starter, going 13-9 with a 3.17 ERA for the Zephyrs and leading the Pacific Coast League with 163 K's. On September 3, he was traded to the Milwaukee Brewers along with Keith Ginter to complete an earlier deal involving Mark Loretta. He debuted for the Brewers on September 19 against the St. Louis Cardinals. Wayne ended the year with a 2-1 record, a 2.62 ERA, and 17 strikeouts in 4 starts for Milwaukee.

After going 10-13 with a 5.50 earned run average and a career-high 116 strikeouts for the Brewers in 2003, Franklin was traded to the San Francisco Giants along with Leo Estrella, for Carlos Villanueva and Glenn Woolard early in 2004. Franklin was converted back to a reliever in 2004 for San Francisco going 2-1 with a 6.39 ERA and 40 strikeouts. He notched his first victory with the Giants on May 21 vs. the Montréal Expos. On July 28 against the San Diego Padres, Wayne was removed from the game with a lower back strain. Franklin was activated from the disabled list on August 18, in between games of a double header against the Expos. He made a spot start for San Francisco in the nightcap, only giving up one run in six innings to earn the victory. Franklin returned to the bullpen for his final 6 appearances, recording a 4.26 ERA. He played in the Venezuelan Winter League in the offseason.

In 2005, Franklin was released by the Giants midway through spring training but was quickly picked up by the New York Yankees as a free agent and assigned to the AAA Columbus Clippers. He posted a 2-3 record and a save in 46 games with Columbus before his contract was purchased by the Yankees in July. He made five appearances out of the bullpen before returning to Columbus in late July. In 2006 Franklin spent time with Tampa Bay Devil Rays and Atlanta Braves AAA teams and returned to the major leagues in August, making his first appearance against the Philadelphia Phillies. Between 2007 and 2009, Wayne had stints with the York Revolution of the independent Atlantic League of Professional Baseball and later signed with Uni-President Lions of Chinese Professional Baseball League in Taiwan and the Chico Outlaws.