Filip Forsberg added a goal and two assists and Thomas Novak also scored for the Predators (5-6-0).
Kevin Lankinen made 33 saves.
Darnell Nurse and Zach Hyman scored in response for the Oilers (2-7-1), who have lost six of their last seven.
Edmonton has yet to record a win at Rogers Place this season.
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Jack Campbell stopped 29-of-34 shots.
The Oilers were first on the board 9:57 into the opening period with a power-play goal. Nurse’s point shot hit the post, then caromed off the back of Lankinen and into the net.
The celebrations were short-lived, however, as Nashville responded just 25 seconds later. A hard-charging Forsberg sped around the net and beat Campbell to the far post with a wraparound.
Predators defenceman Marc Del Gaizo picked up an assist on the play in his NHL debut.
Nashville surged ahead just 23 seconds into the second period. O’Reilly picked up a rebound from a Forsberg shot that went off Campbell’s toe and deposited it into the net.
The pair padded their totals on the power play three minutes later. Forsberg made a pretty pass through the top of the crease to a wide open O’Reilly for his second goal of the game.
Hyman got a goal back on a power play 5:08 into the middle frame. A one-timer from Evan Bouchard ticked off the skate of Hyman and into the net.
Novak restored the Predators’ two-goal edge at 15:15 of the second. He fought off defenceman Vincent Desharnais on a partial breakaway and beat Campbell high to the stick side for his sixth goal of the campaign.
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O’Reilly effectively scored twice on the same shift 8:22 into the third period. He put the puck in on a chip shot from the slot to complete his hat trick.
However, a review determined that a shot by O’Reilly in a scramble earlier in the shift had actually completely crossed the line before being swept out.
In his previous 12 games against Nashville, Oilers forward Leon Draisaitl had recorded 22 goals and 34 points. However, he was held off the scoresheet Saturday. Draisaitl has now gone seven games without a goal, while captain Connor McDavid has gone five games since scoring.
Oilers forward Raphael Lavoie skated in his first game in the big leagues. With Lavoie coming up from Bakersfield of the American Hockey League, defenceman Philip Broberg was reassigned to the Condors.
The Oilers were without Connor Brown (lower body) and Mattias Janmark (shoulder).
The Oilers begin a three-game road trip in Vancouver against the Canucks on Monday.
The Predators play the fourth of a five-game trip in Calgary on Tuesday.