McDonald, without a club, heading home a long throw seven minutes before halftime, while Nicklaw swivelled away from his marker and lashed home a second just after the hour mark in front of 4,000 fans at the National Training Center.
India, boasting a population of 1.2 billion and long dubbed the sleeping giants of world football by FIFA, snatched a 93rd minute consolation when Sunil Chhetri bagged his 50th international goal but it was too little too late.
Guam, coached by Englishman Gary White, now have six points from two matches in the pool, ahead of Oman who beat India away on Thursday. Three-times Asian champions Iran kick-off their campaign later on Tuesday in Turkmenistan.
Prior to this joint World Cup and Asian Cup qualifying campaign, Guam's first and last attempt to qualify for a major tournament ended in a 19-0 loss to Iran in 2000, followed two days later by a 16-0 defeat by Tajikistan.
Guam, ranked 174th by FIFA, face a return to Iran in their next qualifying match in September.
(Wrting by Patrick Johnston in Singapore; editing by Amlan Chakraborty)
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