The City duo were both selected in the starting line-up in Manaus - with Jesus winning his 50th cap - as the five times world champions moved six points clear in the South American standings.
Brazil took an early stranglehold on the game at the Amazonia Arena, storming into a 2-0 lead inside 20 minutes.
Neymar opened their account with a with a 10th minute effort, firing home a low shot after rounding the keeper from Fred’s assist.
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Leeds United’s Raphina then netted his first international strike eight minutes later bundling home from close range.
Raphina doubled his own tally and further extended the hosts’ advantage on 58 minutes, his precise angled shot rounding off a superb counter-attack.
And though Luis Suarez scored a consolation goal for Uruguay with a 77th-minute free-kick, Gabriel Barbosa, who replaced Gabriel Jesus on the hour, set the seal on an emphatic victory with a header seven minutes from time.
