Sanchez opened the scoring for his second goal in three matches and teed up Ander Herrera before half-time as the Red Devils wrapped up their United States tour on a winning note in Miami.
Madrid were playing for the first time since Ronaldo swapped the Champions League holders for Juventus, but Brazilian sensation and debutant Vinicius starred under new head coach Julen Lopetegui on Tuesday.
With Madrid after finalising his €45million move from Flamengo, Vinicius was a shining light as the flamboyant 18-year-old showed glimpses of his enormous potential for the Spanish giants, who completely dominated in the second period after Karim Benzema reduced the deficit on the stroke of half-time.
Jose Mourinho has cut a frustrated figure throughout the pre-season tour, unhappy with the lack of transfer activity and the absence of his stars however United – who were routed 4-1 by Liverpool last week – still manage to field a strong starting XI, which included David de Gea, Fred, Sanchez, Mata, Herrera, Eric Bailly and Luke Shaw.
There were debuts for Vinicius and Alvaro Odriozola, while Benzema and Gareth Bale started Madrid's ICC opener and Lopetegui's bow, with the likes of Toni Kroos, Isco and Marcos Asensio on the bench.
Madrid were stepping out on the field for the first time this pre-season and they, unsurprisingly, looked off the pace and sluggish at times compared to United – playing their fifth match.
United spurned an early chance inside five minutes when Sanchez picked out Mata with a delightful dinked pass but the Spaniard was able to get a shot on target from close range.
Vinicius was a handful for a United back-three featuring Bailly, Timothy Fosu-Mensah and Scott McTominay, but Madrid were overpowered in the first half.
Sanchez broke the deadlock in the 18th minute for his second goal in two matches when Andreas Pereira played through Matteo Darmian and the wantaway Italian cut the ball back for the in-form Chilean to sweep home.
United doubled the lead nine minutes later after Darmian, Mata and Sanchez combined in a sensational team move to tee up Herrera, who fired a half-volley past Kiko Casilla approaching the half-hour mark.
Bale and Benzema struggled to impact proceedings, that was until the latter pulled a goal back in first-half stoppage time when the Frenchman latched onto a Theo Hernandez cross as United's defence switched off.
The second half was in complete contrast to the first as United – who were so dominant in the opening 45 minutes – struggled to string passes together against an improved Madrid.
Ukraine international and teenage goalkeeper Adriy Lunin came on for his Madrid debut following the 19-year-old's €14m arrival in June, while fellow youngster Martin Odegaard was also introduced and wasted a great chance to equalise after blazing over the crossbar.