Making a long-awaited return to the starting line-up from a devastating ACL injury, the 23-year-old struck twice in the first half to secure a 4-1 win in front of a record 25,125 crowd at GIO Stadium in Canberra on Monday night.
The Matildas dominated possession and scoring opportunities, as the midfield pairing of Kyra Cooney-Cross and Clare Wheeler outclassed their South American opponents.
But some nervy moments at the back between Steph Catley and Natasha Prior gave the tourists a sniff, with the dangerous Kishi Nunez a persistent threat.
Regardless, their sixth-straight victory on home soil is a happy parting gift to interim coach Sermanni in his final game in charge of the national side before being replaced by former Lyon boss Joe Montemurro, who was at the game.
Australia were buoyed by the return of captain Catley and Arsenal teammates Caitlin Foord and Cooney-Cross to the starting XI.
The trio were rested for Friday's 2-0 win over Argentina following their Women's Champions League triumph.
Sayer opened the scoring in the 14th minute, popping up at the far post to ram home a deflected volley into the far corner after a searching Kahli Johnson cross evaded a sea of players.
Argentina struggled to play through the Matildas' high press and failed to exert any real pressure when the home side had the ball.
But a seemingly innocuous through-ball left Prior all at sea and after misjudging an interception left the door open for Nunez to steal in behind unchecked.
The diminutive No.9 settled herself, opened herself up and with her right foot curled the ball past a diving Teagan Micah inside the far post, ending a streak of four clean sheets for the Matildas at home.
Still, the home side wouldn't lay down their lead for long.
Foord menaced the visitors all night, constantly harrying the Argentinian defenders in possession and threatening to win the ball high up field.
After nicking the ball near the halfway line, the 30-year-old drove into the Argentinian half before releasing Sayer in behind a retreating opposition defence.
From an unfriendly angle, Sayer picked out the far corner past the outstretched gloves of goalkeeper Solana Pereyra.
As the Argentinians tired in the second half, the chances came thick and fast for the Matildas.
Sayer nearly sealed a hat-trick in the 54th after being sent through by Catley but sprayed her shot from the right high and wide.
Holly McNamara nearly scored her first Matildas goal in the 57th minute but the prolific Melbourne City forward's volley from eight yards out was smartly stopped by a well-positioned Pereyra.
Hometown hero Michelle Heyman, subbed on for Sayer, nearly sent the Canberra crowd into raptures in the 66th minute but was denied by Pereyra with two smart back-to-back saves.
She almost scored again when sent one-on-one with the goalkeeper six minutes later but Pereyra poked the ball away from Heyman's feet, only for it to be turned in by Emily van Egmond.
Heyman finally got her goal in the 83rd minute after Foord again pressured the Argentinian defence into a mistake on the edge of their box, with the veteran squeezing the ball in off a defender from a tight angle.
Debutant Isabel Gomez also managed to get a run late on but failed to make much of an impression with her limited time.
An early concern for Montemurro will be the fitness of youngster Kahli Johnson, who limped from the field late in the first half.
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