Newcastle tore into the visitors from the early stages at St James' Park and new signing Sandro Tonali made their dominance count when he converted Anthony Gordon's inviting sixth-minute cross.
Moussa Diaby cancelled out his fellow debutant's goal within five minutes, though, beautifully controlling a half volley with his weaker foot after Ollie Watkins' flick on.
But at the culmination of a frantic opening period Isak regained the lead for the Magpies as he slid home Sven Botman's cut-back across the box.
Ezri Konsa inexplicably left the ball in his own penalty box.
The competitive clash remained finely poised at the break, however a second from Isak just before the hour mark, capitalising on a defensive error, established a two-goal advantage for the hosts.
Callum Wilson then added a fourth late on before fellow United substitute Harvey Barnes made it five in injury time, ensuring Villa’s miserable 16-match winless record at St. James’ Park continued, stretching back to 2005.
Unai Emery’s side will now be looking to pick up their first points of the season at home to Everton next Sunday.
Sandro Tonali paid off the first instalment of his £52million transfer fee as he marked a fine debut with his first goal and inspired Newcastle to a 5-1 drubbing of Aston Villa.
The 23-year-old Italy international opened the scoring just six minutes into his first competitive appearance for the Magpies and had a hand in two more of their goals as Alexander Isak helped himself to a double and substitutes Callum Wilson and Harvey Barnes struck late on after Moussa Diaby, also making his bow in England’s top flight, had levelled.
However, a hugely entertaining game win was overshadowed by a potentially serious injury to Villa’s England defender Tyrone Mings, who was carried from the pitch on a stretcher to warm applause from a crowd of 52,207 at St James’ Park after going down following a clash with Isak.
Both sides were involved in a six-goal draw in the Premier League Summer Series encounter in July, after Eddie Howe led the Magpies to a spot in the Champions League, whereas Unai Emery's men will partake in the Europa Conference League qualifiers later this month.
Newcastle have won their last 14 league games played at home, while the Villans attempt to win their opening league fixture for the first time in five years.
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