Mills was dismissed by the struggling Astros on Saturday night after a 12-4 defeat to the Arizona Diamondbacks - the latest in a series of losses the young side has suffered.
DeFrancesco, who helped Houston's Triple-A affiliate find success, took temporary charge yesterday - but the losing streak continued as the Astros went down 8-1 to give Arizona a three-game sweep.
General manager Jeff Luhnow said the side needed to shake things up, with the hunt for a new full-time manager now underway.
"Our goal is to assemble the best possible staff to fit the Houston Astros organisation," he said.
"We're going to be working diligently on the search for the remainder of the season or into the off-season, however long it takes. We have no timetable."
Luhnow knows that things won't change overnight, but he's hoping this is the start of something positive for Astros.
"What we want to accomplish for the rest of the season is to win as many games as possible and put ourselves in a position where we have the best staff and group of players as we can possibly have," Luhnow said.
Ichiro Suzuki homered twice and Hiroki Kuroda pitched eight innings of four-hit ball to lead the New York Yankees past Josh Beckett and the Boston Red Sox 4-1.
Derek Jeter had three hits and scored twice for the Yankees, who took two of three from Boston despite playing the entire series without slugger Mark Teixeira.
The AL East leaders won for the ninth time in 12 games, ending a two-year streak of futility against Beckett (5-11).
The right-hander was 5-0 in his previous seven starts against the Yankees since losing to them on Aug. 8, 2010. He kept his team in the game this time, but dropped to 0-4 in his past six outings overall. He is 1-7 in 13 starts since May 20 and has served up seven homers in his past three appearances covering 16 1-3 innings.
Pedro Alvarez hit the game-winning homer and Andrew McCutchen provided some insurance runs as the Pittsburgh Pirates prevailed in their 19th inning of their marathon clash with the St Louis Blues - it ended 6-3.
The Seattle Mariners beat the Minnesota Twins 5-1 to complete their third second-half sweep, while the San Diego Padres snapped a five-game losing run with a 7-1 success over the San Francisco Giants.
The Oakland Athletics maintained their hopes of extending their season with a fourth successive win - 4-0 over the Cleveland Indians, while a four run second inning put the Tampa Bay Rays on the way to an 8-3 victory over the LA Angels.
Kyle Kendrick produced eight scoreless frames in Milwaukee, allowing just three hits and tying a career high with seven strikeouts, as the Philadelphia Phillies downed the Brewers 8-0.
The Atlanta Braves were also blanked, 5-0 by the LA Dodgers, while the injury-hit Colorado Rockies overcame the Miami Marlins 3-2,
The Kansas City Royals scored a fifth win in six games, 5-2 against the Chicago White Sox, to complete a sweep of the AL Central leaders.
The Baltimore Orioles saw off the Detroit Tigers 7-5, while the Washington Nationals sunk the New York Mets 5-2 in a contest which was delayed for two and a half hours by rain.
Elsewhere, the Texas Rangers defeated the Toronto Blue Jays 11-2 and the Cincinnati Reds beat the Chicago Cubs 5-4