Bath hooker Humphreys, who celebrates his 34th birthday next week, won the last of his 33 caps during the 1999 World Cup.
But Wales coach Steve Hansen taken drastic steps to revive the national team following last weekend's defeat by Italy in Rome.
With Humphreys back, Colin Charvis loses the captaincy job and is relegated to the replacements' bench.
But Charvis, capped 51 times, is in good company - fly-half Iestyn Harris, centre Leigh Davies, scrum-half Dwayne Peel, hooker Mefin Davies and flanker Michael Owen have also been dropped.
Pontypridd fly-half Ceri Sweeney will make his first international start as replacement for Harris, while his half-back partner will be Bath's Gareth Cooper.
Also coming into the side are Swansea full-back Kevin Morgan, his club colleague centre Mark Taylor, Llanelli flanker Dafydd Jones and Bath back-row forward Gavin Thomas.
With wing Mark Jones injured, Cardiff's Rhys Williams switches from full-back as Wales seek their first victory over England in Cardiff since 1993.
Humphreys skippered Wales 17 times between 1995 and 1997, winning six and losing 11 of his 17 matches in charge.
Since leaving Cardiff to join Bath last summer, he has enjoyed a new lease of life, turning in several quality performances for the Zurich Premiership club.
But he now faces undoubtedly the biggest challenge of an international career which began in 1995 - attempting to transform Welsh fortunes against the RBS 6 Nations tournament favourites.
Wales: K Morgan (Swansea); R Williams (Cardiff), M Taylor (Swansea), T Shanklin (Saracens), G Thomas (Bridgend); C Sweeney (Pontypridd), G Cooper (Bath); I Thomas (Llanelli), J Humphreys (Bath, capt), B Evans (Swansea), R Sidoli (Pontypridd), S Williams (Northampton), D Jones (Llanelli), M Williams (Cardiff), G Thomas (Bath)
Replacements: G Williams (Bridgend), G Jenkins (Pontypridd), G Llewellyn (Neath), C Charvis (Swansea), D Peel (Llanelli), I Harris (Cardiff), M Watkins (Llanelli)