diff --git a/Library/Homebrew/dev-cmd/bottle.rb b/Library/Homebrew/dev-cmd/bottle.rb
index 0a6d847e46..662739e91f 100644
--- a/Library/Homebrew/dev-cmd/bottle.rb
+++ b/Library/Homebrew/dev-cmd/bottle.rb
@@ -539,8 +539,9 @@ module Homebrew
 
             ohai "Detecting if #{local_filename} is relocatable..." if bottle_path.size > 1 * 1024 * 1024
 
-            prefix_check = if prefix == HOMEBREW_DEFAULT_PREFIX
-              File.join(prefix, "opt")
+            is_usr_local_prefix = prefix == "/usr/local"
+            prefix_check = if is_usr_local_prefix
+              "#{prefix}/opt"
             else
               prefix
             end
@@ -568,11 +569,17 @@ module Homebrew
               relocatable = false if keg_contain?(prefix_check, keg, ignores, formula_and_runtime_deps_names)
               relocatable = false if keg_contain?(cellar, keg, ignores, formula_and_runtime_deps_names)
               relocatable = false if keg_contain?(HOMEBREW_LIBRARY.to_s, keg, ignores, formula_and_runtime_deps_names)
-              if prefix != prefix_check
+              if is_usr_local_prefix
                 relocatable = false if keg_contain_absolute_symlink_starting_with?(prefix, keg)
-                relocatable = false if keg_contain?("#{prefix}/etc", keg, ignores)
-                relocatable = false if keg_contain?("#{prefix}/var", keg, ignores)
-                relocatable = false if keg_contain?("#{prefix}/share/vim", keg, ignores)
+                if tap.disabled_new_usr_local_relocation_formulae.exclude?(formula.name)
+                  keg.new_usr_local_replacement_pairs.each_value do |value|
+                    relocatable = false if keg_contain?(value.fetch(:old), keg, ignores)
+                  end
+                else
+                  relocatable = false if keg_contain?("#{prefix}/etc", keg, ignores)
+                  relocatable = false if keg_contain?("#{prefix}/var", keg, ignores)
+                  relocatable = false if keg_contain?("#{prefix}/share/vim", keg, ignores)
+                end
               end
               skip_relocation = relocatable && !keg.require_relocation?
             end
diff --git a/Library/Homebrew/keg_relocate.rb b/Library/Homebrew/keg_relocate.rb
index 648297ef68..3e75672cd8 100644
--- a/Library/Homebrew/keg_relocate.rb
+++ b/Library/Homebrew/keg_relocate.rb
@@ -84,9 +84,37 @@ class Keg
 
   JAVA_REGEX = %r{#{HOMEBREW_PREFIX}/opt/openjdk(@\d+(\.\d+)*)?/libexec(/openjdk\.jdk/Contents/Home)?}
 
+  sig { returns(T::Hash[Symbol, T::Hash[Symbol, String]]) }
+  def new_usr_local_replacement_pairs
+    {
+      prefix:       {
+        old: "/usr/local/opt",
+        new: "#{PREFIX_PLACEHOLDER}/opt",
+      },
+      caskroom:     {
+        old: "/usr/local/Caskroom",
+        new: "#{PREFIX_PLACEHOLDER}/Caskroom",
+      },
+      var_homebrew: {
+        old: "/usr/local/var/homebrew",
+        new: "#{PREFIX_PLACEHOLDER}/var/homebrew",
+      },
+    }
+  end
+
   def prepare_relocation_to_placeholders
     relocation = Relocation.new
-    relocation.add_replacement_pair(:prefix, HOMEBREW_PREFIX.to_s, PREFIX_PLACEHOLDER, path: true)
+
+    # Use selective HOMEBREW_PREFIX replacement when HOMEBREW_PREFIX=/usr/local
+    # This avoids overzealous replacement of system paths when a script refers to e.g. /usr/local/bin
+    if new_usr_local_relocation?
+      new_usr_local_replacement_pairs.each do |key, value|
+        relocation.add_replacement_pair(key, value.fetch(:old), value.fetch(:new), path: true)
+      end
+    else
+      relocation.add_replacement_pair(:prefix, HOMEBREW_PREFIX.to_s, PREFIX_PLACEHOLDER, path: true)
+    end
+
     relocation.add_replacement_pair(:cellar, HOMEBREW_CELLAR.to_s, CELLAR_PLACEHOLDER, path: true)
     # when HOMEBREW_PREFIX == HOMEBREW_REPOSITORY we should use HOMEBREW_PREFIX for all relocations to avoid
     # being unable to differentiate between them.
@@ -361,6 +389,25 @@ class Keg
   def self.file_linked_libraries(_file, _string)
     []
   end
+
+  private
+
+  sig { returns(T::Boolean) }
+  def new_usr_local_relocation?
+    return false if HOMEBREW_PREFIX.to_s != "/usr/local"
+
+    formula = begin
+      Formula[name]
+    rescue FormulaUnavailableError
+      nil
+    end
+    return true unless formula
+
+    tap = formula.tap
+    return true unless tap
+
+    tap.disabled_new_usr_local_relocation_formulae.exclude?(name)
+  end
 end
 
 require "extend/os/keg_relocate"
diff --git a/Library/Homebrew/tap.rb b/Library/Homebrew/tap.rb
index 989a1fff1d..b3a0855ba4 100644
--- a/Library/Homebrew/tap.rb
+++ b/Library/Homebrew/tap.rb
@@ -26,6 +26,8 @@ class Tap
   private_constant :HOMEBREW_TAP_PYPI_FORMULA_MAPPINGS_FILE
   HOMEBREW_TAP_SYNCED_VERSIONS_FORMULAE_FILE = "synced_versions_formulae.json"
   private_constant :HOMEBREW_TAP_SYNCED_VERSIONS_FORMULAE_FILE
+  HOMEBREW_TAP_DISABLED_NEW_USR_LOCAL_RELOCATION_FORMULAE_FILE = "disabled_new_usr_local_relocation_formulae.json"
+  private_constant :HOMEBREW_TAP_DISABLED_NEW_USR_LOCAL_RELOCATION_FORMULAE_FILE
   HOMEBREW_TAP_AUDIT_EXCEPTIONS_DIR = "audit_exceptions"
   private_constant :HOMEBREW_TAP_AUDIT_EXCEPTIONS_DIR
   HOMEBREW_TAP_STYLE_EXCEPTIONS_DIR = "style_exceptions"
@@ -37,6 +39,7 @@ class Tap
     #{HOMEBREW_TAP_MIGRATIONS_FILE}
     #{HOMEBREW_TAP_PYPI_FORMULA_MAPPINGS_FILE}
     #{HOMEBREW_TAP_SYNCED_VERSIONS_FORMULAE_FILE}
+    #{HOMEBREW_TAP_DISABLED_NEW_USR_LOCAL_RELOCATION_FORMULAE_FILE}
     #{HOMEBREW_TAP_AUDIT_EXCEPTIONS_DIR}/*.json
     #{HOMEBREW_TAP_STYLE_EXCEPTIONS_DIR}/*.json
   ].freeze, T::Array[String])
@@ -1099,6 +1102,19 @@ class Tap
     )
   end
 
+  # Array with formulae that should not be relocated to new /usr/local
+  sig { overridable.returns(T::Array[String]) }
+  def disabled_new_usr_local_relocation_formulae
+    @disabled_new_usr_local_relocation_formulae ||= T.let(
+      if (synced_file = path/HOMEBREW_TAP_DISABLED_NEW_USR_LOCAL_RELOCATION_FORMULAE_FILE).file?
+        JSON.parse(synced_file.read)
+      else
+        []
+      end,
+      T.nilable(T::Array[String]),
+    )
+  end
+
   sig { returns(T::Boolean) }
   def should_report_analytics?
     installed? && !private?