After reaching the 200-goal mark in English football last Sunday, Salah netted twice in each half of a Group A matchday one romp in Cairo. Mostafa Mohamed and Trezeguet also scored.
Djibouti are ranked 154 places below Egypt and survived for only 17 minutes before a low cross eluded two defenders and Salah fired into the net at the far post.
He slammed a penalty over goalkeeper Sulait Luyima and into the roof of the net five minutes later to give record seven-time African champions Egypt a two-goal lead by half-time.
Salah completed his hat-trick with a tap over the line at the far post on 48 minutes and netted again on 69 minutes with a close-range shot into the far corner.
The two-time African Footballer of the Year has scored 52 goals for Egypt, who are seeking a fourth World Cup appearance, with Canada, Mexico and the United States hosting the 2026 finals.
Nigeria are 113 places above Lesotho in the world rankings and were expected to make a winning start in Group C despite the absence through injury of star forward Victor Osimhen.
But Lesotho stunned the nome crowd in the southeastern city of Uyo by taking a 56th-minute lead when Motlomelo Mkhwanazi rose at the far post to nod home after a corner.
Nigeria equalised 11 minutes later when Semi Ajayi, who plays for English second-tier club West Bromwich Albion, scored with a powerful header off a corner taken by captain Kelechi Iheanacho.
Aided by a second-minute own goal in Algiers, four-time World Cup qualifiers Algeria defeated lowly ranked Somalia 3-1 in Group G.
After a low cross struck Ahmed Abdi and entered the Somali net, Baghdad Bounedjah doubled the lead before half-time.
Yusuf Ahmed halved the deficit midway through the second half and Algeria had to wait until 10 minutes from time before restoring a two-goal lead through Islam Slimani.
Kenya, back in international football after a FIFA ban for political interference prevented them playing in 2024 Africa Cup of Nations qualifying, lost 2-1 away to Gabon in Group F.
Masoud Juma put Kenya ahead just before half-time in Franceville, Denis Bouanga levelled on the hour mark and Guelor Kanga snatched an 88th-minute winner for the home side.
