The easiest way is a RPG (rocket propelled grenade) or rocket launcher to his weak point, but there is another shortcut, where after Chris and Sheva are reunited on the center island in the volcano and Wesker's weak point is on his chest and not his back, have Chris go behind Wesker, where he will be given the option to restrain Wesker. Then have Sheva walk up to Wesker's weak point, where she whill be given the option to attack it with her knife. Do it correctly and Wesker will instantly die.
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