Justin Schultz, Jordan Eberle and Ryan Nugent Hopkins also had a goal and an assist in the game and Nail Yakupov also scored for the Oilers (16-32-7), who captured just their fifth win in the last 22 games and have had five losing streaks reach five games or more this season.
David Legwand responded for the Predators (23-23-8), who have lost two in a row.
Edmonton started the scoring three minutes into the game as Jesse Joensuu saw Schultz streaking in from the point and hooked a pass to the defender for a hard shot that beat Predators starter Carter Hutton.
Nashville tied the game up with four-and-a-half minutes to play in the opening period as Legwand elected to shoot it himself on a two-on-one break and picked the top corner past Oilers goalie Ben Scrivens.
The Oilers went into the dressing rooms on a positive note after a goal with 12 seconds left in the first period as Taylor Hall sent a great pass through the legs of defender Roman Josi to give Eberle an easy redirection into the net from the doorstep.
It was a significant goal, as the Predators came into the game with a 1-16-2 record when trailing after the first period.
Nashville thought it had clawed even just 48 seconds in to the second period, but Taylor Beck was called for goalie interference for running Scrivens over as he chipped the puck in and the goal was disallowed.
Edmonton went up by two goals midway through the second period as Smyth picked up the rebound to a long Corey Potter shot in the crease and hooked it past Hutton. It was Smyth's 125th power-play goal as an Oiler, tying him for the team's all-time list with Wayne Gretzky and putting him one back of leader Glenn Anderson. Smyth is also one goal back of hitting the top 100 list of all-time NHL scorers.
Edmonton made it 4-1 with three minutes left in the second frame as Sam Gagner hit a trailing Yakupov on an odd-man rush and the 2012 first overall NHL draft pick sent home his 10th of the season.
The Predators turned the third period into something of a shooting gallery at the Edmonton net and thought they had finally been rewarded on what looked to have been a Craig Smith goal, but once again Beck was called for goaltender interference as he was actually lying on top of Scrivens when the puck trickled across the line.
The Oilers put the game away for good with four-and-a-half minutes left to play after some quick passing on the power play led to Nugent-Hopkins' 15th goal of the season.
The Oilers return to action on Monday night with a quick trip to Vancouver. The predators conclude a four-game trip in Winnipeg on Tuesday.
Notes: It was the second of three meetings between the two clubs this season. Edmonton won the first game 3-0 on Nov. 28 with Ilya Bryzgalov earning the shutout… It was the first meeting between the teams since a trade on Jan. 15 that saw goalie Devan Dubnyk sent from the Oilers to the Preds in return for forward Matt Hendricks. Dubnyk has not had a strong start in Nashville, allowing nine goals in his two starts, and was not selected to play against his former team… The Oilers were without captain Andrew Ference, who suffered a head injury in their previous game against Phoenix. Forward Ales Hemsky also remained out with an ankle injury… Predators goalie Pekka Rinne continues to be on injured reserve with a hip injury… Nashville forward Eric Nystrom was coming off a rare four-goal performance against the Calgary Flames on Friday.