Manchester City's David Silva fired in the opener from Jordi Alba's pass after 13 minutes before Thiago Alcántara laid on the second for Sevilla's Vitolo, whose shot squirmed under Ofir Marciano in first-half stoppage time in Gijon.
Alcántara was the creator for Spain's third - six minutes into the second half, nodded in by Chelsea top-scorer Diego Costa from Alcántara's corner.
Leor Rafaelov gave Israel a lifeline, pulling one back in the 71st minute, but an 88th strike from Isco sealed Israel's fate, wrong-footing Marciano to ensure Spain extended their unbeaten record and stay top of the group.