The Surrey side occupy the fifth and final place in the drop zone and were desperate for a win to keep up their hopes of securing a place in next season's second tier.
Manchester stormed into the lead after just three minutes when fly-half Richard Wainwright ran down an attempted clearance and scored under the posts.
But Esher hit back strongly and were 28-10 ahead at the break following a George Lowe hat-trick and another from Tom Lozides.
Manchester had most of the possession in the second half and added more points through Edward Styles and a penalty try. However, Joseph Knowles and another Lowe try saw Esher clinch victory 40-28.
Meanwhile, Sedgley Park were torn apart at soaraway leaders Leeds. The Yorkshirmen ran in 10 tries in an emphatic 66-0 win.
In National League Three North, Macclesfield lost ground after a 16-10 defeat at Leicester Lions.
A second-half converted try from Jonathon Keep kept the Blues within striking distance but the Lions wrapped up the points with a try 10 minutes from time.
Other results: North 1 - Stockport 55 Darlington 10. North 2 West - Lymm 37 Broughton Pk 6, New Brighton 22 Altrincham Kersal 15, Northwich 15 Blackburn 11, Rochdale 14 Leigh 7, Rossendale 12 Wilmslow 8. N Lancs/Cumbria - Heaton Moor 18 Burnley 3, Oldham 10 Aldwinians 16. N Lancs 1 - Ashton-under-Lyne 3 Eccles 21, Bolton 9 De la Salle 30, Bury 8 Didsbury Toc H 3, Furnes 37 Old Bedians 6, Garstang 5 Trafford MV 10. S Lancs/Cheshire 1 - Burnage 13 Sale 11, Dukinfield 17 Wigan 28, Ormskirk 15 Widnes 39, Winnington Pk 3 Bowdon 32. S Lancs/Cheshire 2 - Ruskin Park 26 Anselmians 16, Sefton 28 Ashton-on-Mersey 10, Trentham 17 Warrington 12. S Lancs/Cheshire 3 - Marple 40 Holmes Chapel 20, Newton-le-Willows 14 Knutsford 37, Oldershaw 29 St Edward's OB 19.
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