With captain Harry Kane rested and Tammy Abraham one of three players alongside Jadon Sancho and Ben Chilwell absent for breaching coronavirus protocol rules, Calvert-Lewin was selected by Gareth Southgate to lead the line.
The in-form Everton striker headed home from Jack Grealish's sublime cross before Conor Coady doubled the lead eight minutes after the break.
Danny Ings then celebrated his first international goal, marking the first time three England players all scored a maiden goal in the same game since 1963, as the Three Lions completed a clinical if not textbook performance ahead of tougher assignments.
3 - Tonight is the first time three players (Calvert-Lewin, Coady and Ings) have all scored their first England goals in the same game since June 1963 vs Switzerland (Tony Kay, Johnny Byrne and Jimmy Melia). Fresh. pic.twitter.com/GxL9Zpo12C— OptaJoe (@OptaJoe) October 8, 2020
An England XI boasting just 54 appearances – the lowest since 1980 – started nervily and Kieffer Moore dragged a volley wide after a poor headed clearance from debutant Bukayo Saka.
But Calvert-Lewin marked a fine England bow by nodding home from six yards in the 26th minute when Grealish, making his first Three Lions start, hung up a peach of a cross after tying Ethan Ampadu in knots.
The lead was doubled when Kieran Trippier – who became England's 123rd skipper in the absence of Kane – produced a fine free-kick that Coady expertly half-volleyed past Wayne Hennessey from close range.
Wales had no way back just after the hour when Tyrone Mings headed a corner back across the face of goal for Southampton striker Ings to steer acrobatically home with a lovely overhead effort.
Hennessey made a couple of smart stops to deny Ainsley Maitland-Niles and Ings late on to ensure no further damage for Wales.
What does it mean? England have striker options
For a long time, Kane has been England's solitary go-to up front but the form of Calvert-Lewin and more minutes and a maiden international goal for a revitalised Ings means Southgate now has plenty of striking options.
Calvert-Lewin has been in sublime form for Premier League leaders Everton this term and now has 10 goals in seven appearances for club and country. This was a deserved opportunity and if he continues in this form, he surely is a certainty for future squads.
10 - Dominic Calvert-Lewin now has 10 goals in seven appearances for club and country this season. Impressive. pic.twitter.com/XClr6HP1yy— OptaJoe (@OptaJoe) October 8, 2020
Giggs' case for the defence crumbles
Wales boss Ryan Giggs will have been encouraged by a first half in which Wales caused England issues, particularly Cardiff City striker Moore who went off injured towards the end of the opening 45 minutes. But usually consistent full-back Ben Davies, who lost possession 12 times, was not always at the races and centre-back pairing Chris Mepham and Joe Rodon gave England's forwards far too much space.