Horton's closest competitor was Tyler Perry's Meet The Browns, from Lionsgate. Grossing an estimated $20m for the weekend, the African-American dramedy was the best performer among three new wide releases.
Opening on just 266 screens, meanwhile, Mexican drama Under The Same Moon grossed $2.6m, the biggest North American opening ever for a Spanish-language film, according to co-distributors Fox Searchlight and the Weinstein Company (TWC).
Easter is not considered a major moviegoing weekend in the US and this year proved to be especially quiet: aggregate gross for the weekend's top ten films was down almost 10% on the total for Easter weekend 2007.
Expanding slightly to better accommodate children and the many parents who also had Friday off, Dr Seuss' Horton Hears A Who! took its $25.1m from 3,961 theatres, for a per-theatre average of $6,336. Compared to previous animated offerings from Fox and its Blue Sky Studios, the film's second-weekend drop was bigger than the 32% fall-off for Ice Age and the 42% for Robots but smaller than the 50% for Ice Age 2.
Meet The Browns, which stars Angela Bassett and also features the return of writer-director-producer-performer Tyler Perry's hugely popular Madea character, took its weekend gross from 2,006 theatres, giving it a per-theatre average of $9,975, the highest in the top ten.
The debut continued Perry's streak of box office success but was slightly smaller than openings for his earlier Lionsgate-distributed releases such as Why Did I Get Married' and Diary of a Mad Black Woman.
In third place on the chart, Fox's Shutter, the US version of the similarly-titled 2004 Thai horror movie, opened with an estimated $10.7m from 2,753 theatres (average - $3,886). Produced by Fox and Regency Enterprises with Joshua Jackson and Rachael Taylor starring for director Masayui Ochiai, the Japan-set PG-13 chiller beat most box office predictions in spite of bad reviews.
Paramount's Judd Apatow-produced PG-13 high school comedy Drillbit Taylor, with Owen Wilson starring for director Steven Brill, got marginally better reviews but fell short of some expectations, opening in fourth with an estimated $10.2m from 3,056 theatres (average - $3,337).
Under The Same Moon (La Misma Luna), the Spanish-language drama about Mexico-US immigration acquired at Sundance and jointly distributed by Fox Searchlight and TWC, sneaked into the top ten with its estimated $2.6m from 266 theatres (for an impressive average of $9,781 per theatre). Having opened on Wednesday in a number of specialised and heavily Hispanic markets, the film ended the weekend with a five-day gross of $3.3m (average - $12,500).
TWC said the film, directed by Patricia Riggen and with a cast including Adrian Alonso, Kate Del Castillo and America Ferrera, beat the Spanish-language opening record set last August by the $1.6m debut of Ladron Que Roba A Ladron (distributed in the US by Lionsgate).
Among holdovers, Summit's Never Back Down dropped a reasonable 44% in its second weekend to take an estimated $4.9m from 2,729 theatres (average - $1,781) while Universal's Doomsday fell out of the top ten after diving 56% to an estimated $2.2m from 1,938 theatres.
In their third weekends, Warner's 10,000 BC was down 48% to an estimated $8.7m, Buena Vista's College Road Trip was off 41% to an estimated $4.6m and Lionsgate's The Bank Job slipped only 19% to an estimated $4.1m.
Next weekend's wide releases are: Columbia's Las Vegas card-counting drama 21, with Jim Sturgess, Kate Bosworth and Kevin Spacey starring and Robert Luketic directing; Picturehouse comedy Run, Fat Boy, Run, starring Simon Pegg and directed by David Schwimmer; Paramount's Iraq war-themed drama Stop-Loss, with Ryan Phillippe starring for director Kimberly Peirce; and TWC/MGM's David Zucker spoof Superhero Movie, featuring Leslie Nielsen and Tracy Morgan.
Estimated Top 10 North America March 21-23, 2008
Film (Dist)/Int'l dist/Est wkd gross/Est total to date
1 (1) Dr Seuss' Horton Hears a Who! (Fox) Fox Int'l $25.1m $86.5m
2 (-) Tyler Perry's Meet The Browns (Lionsgate) n/a $20m -
3 (-) Shutter (Fox) Fox Int'l $10.7m -
4 (-) Drillbit Taylor (Paramount) PPI $10.2m -
5 (2) 10,000 BC (Warner Bros) WBPI $8.7m $76.1m
6 (3) Never Back Down (Summit) Summit $4.9m $16.8m
7 (4) College Road Trip (Buena Vista) WDSMPI $4.6m $32m
8 (6) The Bank Job (Lionsgate) Arclight Films $4.1m $19.4m
9 (5) Vantage Point (Sony) SPRI $3.8m $65.3m
10 (-) Under the Same Moon (TWC/Fox Searchlight) Fox Int'l $2.6m $3.3m