Goals from Craig Dawson, Declan Rice and Jarrod Bowen secured a surprisingly comfortable 4-1 aggregate success in France, setting up a last-four meeting with Eintracht Frankfurt, which stunned Barcelona in its match.
The German side was, in fact, the opposition the last time the Hammers reached this stage of continental competition – that tie coming en route to defeat in the final of the 1976 edition of the European Cup Winners' Cup.
But there will be hopes of going one better in Europe more than four decades on after such a convincing win against elite opposition.
With Lyon supporters creating an intimidating atmosphere pre-match, West Ham wasted little time in showing it would not be cowed, Pablo Fornals bursting in behind to shoot wide with just 15 seconds on the clock.
But Lyon responded well, Karl Toko Ekambi smashing the post after quick feet in the box before Houssem Aouar saw a shot blocked on the line.
The hosts were also controlling possession, and so when Ekambi kneed a Malo Gusto cross goalward soon after, it felt like the opener was coming.
Unfortunately for Lyon, it was at the other end, with sheer desire from Dawson allowing him to beat all others to a near-post Fornals corner and head home.
Not content to sit on their lead, West Ham then doubled the advantage before the break as a low Rice shot from the edge of the box found the back of the net after taking a nick off Castello Lukeba.
That late blow prompted Peter Bosz to roll the dice, Lucas Paqueta and Mateus Tete coming on at half-time to replace Tanguy Ndombele and Romain Faivre.
But there was to be no quick fix, with Bowen breaking free just three minutes after the restart and producing a cool right-footed finish to all but settle the tie.
Lyon did not stop trying to make things interesting from there on in, its best chance seeing Gusto force Alphonse Areola to push a powerful shot around the post.
But a first failure to trouble the scoresheet at home in the UEFA Europa League since the 2013-2014 season ultimately ensured that West Ham had little trouble seeing out the win.