David Silva and Vitolo both registered in the first period, before Diego Costa and Isco netted in the second as La Roja, who shipped just their second goal in Group G late on, moved onto 13 points in the section.
As expected, Chelsea striker Costa led the line for the home side, while Vitolo and Silva were also handed starts in Spain's 4-3-3 formation, which also had a place for Andres Iniesta despite his injury problems this season.
As for Israel, the top scorer in their squad - Brighton & Hove Albion's Tomer Hemed - was only on the bench, with the central striking position being handed to Guangzhou's Eran Zahavi, who skippered his country once again. Hibernian goalkeeper Ofir Marciano, meanwhile, was selected between the sticks.
It was the visitors that registered the game's first shot on target inside the opening two minutes, but Zahavi's effort was always comfortable for Manchester United goalkeeper David de Gea.
Spain's first real chance of the night came in the sixth minute when Thiago Alcantara struck one towards the top corner, but the ball rattled against the crossbar as the Bayern Munich midfielder was denied a spectacular goal.
Israel remained a threat down the other end, however, and a mistake from Gerard Pique allowed Zahavi to break into a one-on-one situation with De Gea, although the Barcelona centre-back got back to put the Israel captain off at the final moment, and the ball moved wide of the post.
The pressure continued to build on the Israel goal as play developed though, and Spain made the breakthrough in the 13th minute of action when Jordi Alba threaded a pass into Silva, who turned inside the Israel box and smashed the ball through the legs of Marciano.
Iniesta was next to come close for Spain in the 22nd minute after a cute Silva pass had found the Barcelona midfielder inside the Israel box, but his first-time effort was just wide of the near post.
Zahavi remained Israel's biggest threat, and the away side's captain had another half-chance in the 24th minute after breaking into a dangerous position, but his effort from distance just bounced wide of De Gea's post.
Spain continued to dominate the ball in the final 15 minutes of the first period, but Israel had a chance to level in the 44th minute when Lior Refaelov met a cross from Rami Gershon, only to be denied by De Gea.
There was to be more drama in the final stages of the first half, however, with Spain doubling their lead through Vitolo after the Sevilla attacker's low effort somehow found a route past Marciano in what was a howler from the goalkeeper.
Spain should have made it 3-0 early in the second period when Dani Carvajal found Costa with a cross from the right, but the Chelsea striker could only head wide of Marciano's post.
Israel were almost given a route back into the match in the 48th minute when a scramble inside the Spain box led to Thiago deflecting the ball towards his own goal, but De Gea was on hand to make his second smart save of the night.
The visitors were always vulnerable down the other end, however, and Spain scored their third of the night in the 51st minute when Costa rose highest inside the Israel box to head a corner past Marciano from close range.
Silva should have scored his second of the night just before the hour when Costa's header dropped for the Manchester City attacker inside the Israel box, but he could only strike the post with a powerful effort.
Zahavi continued to occupy Spain's two centre-backs, although it became a damage limitation exercise for Israel in the second period as they looked to avoid a heavy defeat in Gijon.
Hemed was thrown on for Israel in the 64th minute as the visitors made their second enforced change of the night, but the Brighton striker found it difficult to get involved as Spain continued to dominate possession of the ball.
Isco followed Koke off the Spain bench as head coach Julen Lopetegui demonstrated the quality he had in reserve, and the home side continued to put the pressure on Israel as they looked for a fourth goal in the final 20 minutes.
It was Israel that scored the game's fourth goal in the 76th minute, however, when Refaelov found the top corner after Gershon's header from a set piece had hit De Gea's post.
Spain should have scored a fourth late on when Silva broke through before threading a ball towards Vitolo, but the cross just had too much weight and the Sevilla attacker, who was later replaced by Iago Aspas, could not convert.
La Roja were not to be denied, however, and scored a fourth in the 88th minute when Isco, whose Real Madrid future continues to come under discussion, carefully threaded the ball into the bottom corner.
Next up for Lopetegui's side is a glamour friendly with France in Paris on March 28.