A first half strike from Fredi Kanoute wasn't enough to prevent Hammers from slipping to defeat against Lawrie Sanchez's men, who were 2-0 up inside 25 minutes and added a third seven minutes from time.
The defeat was all the more frustrating given the fact that Glenn Roeder had been able to field a stronger side than the one that held Swedish champions Djurgardens IF to a 0-0 draw on Thursday.
The Hammers boss had welcomed back Sebastien Schemmel, Ian Pearce and Don Hutchison after all three had suffered minor injuries in recent weeks, and there was also a place on the substitutes' bench for Michael Carrick, finally recovered after the hernia operation he underwent in April.
The return of Pearce meant a defensive reshuffle for Hammers, as Christian Dailly reverted to left-back, while Youssef Sofiane switched to a left-midfield role in a 4-4-2 formation following his impressive displays in Scandinavia last week.
The young French attacker was arguably Hammers' most effective player in a lively first half, as he showed confidence on the ball, ran at his marker whenever possible, and saw a couple of fierce efforts saved by Wycombe goalkeeper Steve Williams.
Despite making the better start, though, Roeder's men couldn't find an early goal to damage the confidence of the second division side, and it was the hosts who took the lead on 20 minutes.
Former Hammer Darren Currie curled in a cross from the left that David James came out to clear, but the England keeper completely fluffed his punch and the ball dropped to another ex-Upton Park hopeful, Gavin Holligan, who poked home from six yards out.
Hammers almost replied immediately, when Joe Cole's deep cross was headed on by Hutchison, but Williams gathered the ball just as Jermain Defoe was about to pounce, and just moments later, Wycombe doubled their tally, as a long throw from Richard Harris on the left was met by Roger Johnson, whose firm header cannoned in off the post.
Again the visitors created a chance to pull one back soon after, and again it was Cole the provider, but his inch-perfect pass was steered wide by Defoe, who endured a difficult night up against Wycombe defender Marc Rogers.
Hammers finally pulled a goal back just five minutes before the break, when Cole released Defoe and the young striker's low shot was blocked by Wycombe keeper Steve Williams, only for Kanoute to collect the rebound and smash the ball into the roof of the net from four yards out.
That clearly lifted the visitors, and they started the second half in much more determined mood. Shaun Byrne replaced Pearce, who went off as a precaution, and the young full-back added further attacking momentum to the left hand side.
On 49 minutes, Kanoute had a chance to grab his second of the night when he skipped into the area unchallenged, but the Frenchman created a difficult angle for himself and saw his effort blocked by a defender.
As so often, Hammers' best moves were orchestrated by Cole in the centre of midfield, and on 54 minutes the captain created another glorious chance for Defoe when he slipped in a clever reverse pass, but again the England under-21 striker shot wide.
On 63 minutes, Carrick made a welcome introduction, replacing the tired Lee, and the young Geordie midfielder almost created an equaliser within 10 minutes of coming on, as his neat pass found Cole, who took one touch inside the penalty area and curled in a shot that crashed off the bar. The loose ball reached Sofiane, whose dipping volley was heading for the top corner until Williams tipped it over.
As they surged forward in search of the elusive second goal, Hammers unsurprisingly left gaps at the back, and Wycombe made sure of the victory with seven minutes remaining when a cross from the right was turned in by substitute Lewis Cook, whose slightly mis-hit left foot volley found the top corner.
On a rainy and dismal night in Wycombe, things weren't much better on the pitch for Hammers, and Roeder's team will have to produce a more disciplined performance if they are to finish their pre-season preparations on a high note against Dutch champions PSV Eindhoven on Friday night.
Wycombe: Williams, Senda, Vinnicombe, Johnson, Rogers, Currie
(Cook 63), Simpson (Brown 83), Mapes (Bulman 70), Harris (Harding
70), Holligan (Patterson 28), McSporran (Roberts 63). Subs
unused: Matthews, Simpemba, Oliver, Thompson.
Hammers: James, Schemmel, Pearce (Byrne 46), Repka, Dailly, Hutchison, Lee (Carrick 63), Cole, Sofiane, Kanoute (Garcia 63), Defoe. Subs unused: McMahon, Ferdinand, McClenahan.