England international Kane, the Premier League's joint top scorer with 19 goals, had to hobble off after falling awkwardly and suffering an ankle injury in a sixth-minute challenge with defender Jake Cooper during their sixth round tie.
Yet his absence was not missed on the day as Spurs' South Korea striker Son Heung-min netted a brilliant hat-trick and Kane's replacement Christian Eriksen also scored a beauty before Dele Alli and substitute Vincent Janssen got in on the act.
It all made for an emotional occasion at Spurs' storied 118-year-old ground which they will leave for a season at the end of the campaign before returning to a new stadium at the site.
Third-tier side Millwall had beaten three top-flight teams en route to the quarter-finals but Premier League title chasers Spurs dominated them from the outset at the grand old ground where they have not lost all season.
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Eriksen made the key breakthrough with a brilliant snap shot on the turn on the half-hour mark before Son crashed home a thunderous left-foot strike 10 minutes later.
The Korean then struck a sweet first-time, right-foot volley from Kieran Trippier's through ball in the 54th before Alli netted his 16th of the season in all competitions, a tap-in after a well-crafted move, in the 72nd.
The icing on the cake was a first goal from open play in the 79th minute for Spurs' under-achieving striker Janssen. The Dutchman may yet be needed in their title challenge if Kane, who will be assessed on Monday, is out of action for long.
Son's third came in stoppage time, a volley that slipped through the clutches of hapless Millwall keeper Tom King.
"A hat-trick from Son and Janssen scored... the team was good. We need to congratulate them, they were waiting for the opportunity and they took it and stepped up," said Spurs manager Mauricio Pchettino.
"In football you always need to be ready. Not only him (Janssen) but different players too will have the opportunity to play more and they need to be ready."
The array of glorious goals, particularly from man-of-the-match Son and Eriksen, was a fitting way for Spurs to say farewell to Cup competition at the old White Hart Lane.
The semi-final will be at Wembley Stadium, where they plan to play home games next term before moving into a new 800 million pounds ($972 million), 61,000-seat stadium next door to the current ground in 2018-19.
They will be joined in the highest-quality of last four draws by Arsenal and Manchester City, who won their quarter-finals on Saturday, and Chelsea or Manchester United, who meet in the remaining sixth round tie at Stamford Bridge on Monday.
($1 = 0.8226 pounds)
(Reporting by Ian Chadband; Editing by Toby Davis and Ken Ferris)
