Nick Markakis led the charge by going 2-for-4 and driving in three runs for Baltimore (42-55), which snapped a record 11-game losing streak in Boston dating back to July 12, 2008.
Sunday's setback dropped the Red Sox (57-40) 2 1/2 games behind the American League East-leading Yankees, who were 7-5 winners over the Athletics at Yankee Stadium.
Five days removed from a start against Texas in which the Rangers tagged him for six runs in 5 2/3 innings, Smoltz was roughed up once again on Sunday, marking just the second time in his decorated career that he's allowed at least six earned runs in consecutive outings.
"People are going to write whatever they want to write, and rightfully so," said Smoltz, who fell to 1-4. "It's the highest ERA [7.04] I've ever had, but what I can tell you is that each time out, my stuff has got better and better. I'm just in a position where, until I execute, I'm going to have to deal with [criticism].
"My stuff is not done. My results might put me in a category where they're going to talk about it, but with the exception of some hits, I'm tired of tipping my hat to the hitters."
After plating Brian Roberts with a first-inning sacrifice fly, Markakis ignited a two-out rally in the third. His RBI double to right-center was the first of three consecutive run-scoring hits for Baltimore, which built a 4-0 lead through four innings.
Felix Pie delivered a two-out RBI double one inning later, and Markakis capped the scoring against Smoltz in the sixth by clocking a solo home run to right.
The Red Sox cracked the scoreboard in the bottom of the frame on a sac fly from Jed Lowrie, but they would score just once more, in the eighth inning against the Baltimore bullpen.
A 24-year-old rookie making his first career start at Fenway Park, Orioles right-hander David Hernandez (3-2) stymied the Sox's bats to the tune of one run on five hits over seven innings.
"This is special," Baltimore manager Dave Trembley said. "For him to come in here after he pitched in Yankee Stadium [on Monday] says a lot about how far he's come and what he means to our future. He pitched with confidence and poise, and he didn't get rattled one bit."
One day after a seven-run output that seemed to signal a resurgence from the slumping Boston offense, luck was not on the side of the Red Sox on Sunday.
"There were a lot of good swings today," said David Ortiz, who finished 0-for-4. "But nothing happened."
The Orioles made plenty happen against a frustrated Smoltz, who continues to search for answers one month into his stint in the Red Sox's rotation.
"Some changes have to be made," Smoltz declared. "But I'll grind it out until someone takes the ball from me. After the mental toughness it took for me to get to this point, I don't think you can just disappear.
"I'm not a quitter."
Though they fell to 1-5 in games Smoltz has started this season, the Red Sox refuse to believe the likely future Hall of Famer will continue to struggle.
"His career's not over," Boston manager Terry Francona said. "I don't think we look at it like that. I think he's going to be just fine. I've been wrong before, but I don't think I'm wrong this time."