Having stormed past Ferencvaros in the play-off round after a superb second-leg display on home soil, Plzeň knew the importance of a positive start against their Italian visitors.
Miroslav Koubek’s side thought they’d taken an early lead when Pavel Sulc fired a brilliant strike into the far corner, only for VAR to disallow the goal for a controversial offside.
Grateful for that reprieve, Lazio soon compounded the hosts’ frustration, with Alessio Romagnoli converting Tijjani Noslin’s flicked header at the back post for his second Europa League goal of the season.
The Biancocelesti continued to edge proceedings as the first half progressed, but clear-cut chances came at a premium as the Plzen rearguard held firm under pressure. Boulaye Dia saw a low effort comfortably saved by Martin Jedlicka, while Isaksen made a mess of a glorious one-on-one opportunity when his heavy touch allowed Jedlicka to collect inside the box.
Determined to find a route back into the contest, the hosts came flying out the blocks at the start of the second half and their pressure was duly rewarded when Lukas Kalvach’s inviting free-kick was clinically headed home by Rafiu Durosinmi.
Buoyed by that goal, Plzen came close to adding a quickfire second, as Durosinmi’s powerful strike from 12 yards was parried away smartly by Ivan Provedel.
With time ticking into the final half-hour, Koubek’s men continued to commit numbers forward in pursuit of a winning goal, and their hopes were boosted in the 77th minute when Nicolo Rovella was dismissed for a high boot on Sulc after a lengthy VAR review.
Armed with the numerical advantage for the closing stages, Plzen piled the pressure on Lazio but found no way through.
And despite a second red card for the visitors following an ugly lunge from Samuel Gigot, Marco Baroni’s side snatched a remarkable winning goal in the eighth minute of stoppage time when Isaksen swept a glorious finish into the far corner, giving Lazio the most unlikely of leads heading into next week’s return leg in Rome.
Flashscore Man of the Match: Alessio Romagnoli (Lazio)