diff --git a/lib/spack/spack/binary_distribution.py b/lib/spack/spack/binary_distribution.py
index d22572d8a41..7c62c58cb19 100644
--- a/lib/spack/spack/binary_distribution.py
+++ b/lib/spack/spack/binary_distribution.py
@@ -42,7 +42,7 @@
 import spack.util.url as url_util
 import spack.util.web as web_util
 from spack.caches import misc_cache_location
-from spack.relocate import utf8_path_to_binary_regex
+from spack.relocate import utf8_paths_to_single_binary_regex
 from spack.spec import Spec
 from spack.stage import Stage
 
@@ -694,13 +694,10 @@ def before_visit_symlinked_dir(self, root, rel_path, depth):
         return False
 
 
-def file_matches_any_binary_regex(path, regexes):
+def file_matches(path, regex):
     with open(path, "rb") as f:
         contents = f.read()
-    for regex in regexes:
-        if regex.search(contents):
-            return True
-    return False
+    return bool(regex.search(contents))
 
 
 def get_buildfile_manifest(spec):
@@ -734,8 +731,8 @@ def get_buildfile_manifest(spec):
     prefixes.append(spack.hooks.sbang.sbang_install_path())
     prefixes.append(str(spack.store.layout.root))
 
-    # Create a list regexes matching collected prefixes
-    compiled_prefixes = [utf8_path_to_binary_regex(prefix) for prefix in prefixes]
+    # Create a giant regex that matches all prefixes
+    regex = utf8_paths_to_single_binary_regex(prefixes)
 
     # Symlinks.
 
@@ -767,10 +764,9 @@ def get_buildfile_manifest(spec):
                 data["binary_to_relocate_fullpath"].append(abs_path)
                 continue
 
-        elif relocate.needs_text_relocation(m_type, m_subtype):
-            if file_matches_any_binary_regex(abs_path, compiled_prefixes):
-                data["text_to_relocate"].append(rel_path)
-                continue
+        elif relocate.needs_text_relocation(m_type, m_subtype) and file_matches(abs_path, regex):
+            data["text_to_relocate"].append(rel_path)
+            continue
 
         data["other"].append(abs_path)
 
diff --git a/lib/spack/spack/relocate.py b/lib/spack/spack/relocate.py
index 667e8de4e0c..0d7525eb05f 100644
--- a/lib/spack/spack/relocate.py
+++ b/lib/spack/spack/relocate.py
@@ -747,9 +747,13 @@ def relocate_links(links, orig_layout_root, orig_install_prefix, new_install_pre
 def utf8_path_to_binary_regex(prefix):
     """Create a (binary) regex that matches the input path in utf8"""
     prefix_bytes = re.escape(prefix).encode("utf-8")
-    prefix_rexp = re.compile(b"(?<![\\w\\-_/])([\\w\\-_]*?)%s([\\w\\-_/]*)" % prefix_bytes)
+    return re.compile(b"(?<![\\w\\-_/])([\\w\\-_]*?)%s([\\w\\-_/]*)" % prefix_bytes)
 
-    return prefix_rexp
+
+def utf8_paths_to_single_binary_regex(prefixes):
+    """Create a (binary) regex that matches any input path in utf8"""
+    all_prefixes = b"|".join(re.escape(prefix).encode("utf-8") for prefix in prefixes)
+    return re.compile(b"(?<![\\w\\-_/])([\\w\\-_]*?)(%s)([\\w\\-_/]*)" % all_prefixes)
 
 
 def unsafe_relocate_text(files, prefixes, concurrency=32):
diff --git a/lib/spack/spack/test/relocate.py b/lib/spack/spack/test/relocate.py
index 42e392c1ba8..8e8819ca48a 100644
--- a/lib/spack/spack/test/relocate.py
+++ b/lib/spack/spack/test/relocate.py
@@ -20,7 +20,7 @@
 import spack.store
 import spack.tengine
 import spack.util.executable
-from spack.relocate import utf8_path_to_binary_regex
+from spack.relocate import utf8_path_to_binary_regex, utf8_paths_to_single_binary_regex
 
 pytestmark = pytest.mark.skipif(sys.platform == "win32", reason="Tests fail on Windows")
 
@@ -480,9 +480,24 @@ def test_fixup_macos_rpaths(make_dylib, make_object_file):
 
 
 def test_text_relocation_regex_is_safe():
-    assert (
-        utf8_path_to_binary_regex("/[a-z]/")
-        .search(b"This does not match /a/, but this does: /[a-z]/.")
-        .group(0)
-        == b"/[a-z]/"
-    )
+    # Test whether prefix regex is properly escaped
+    string = b"This does not match /a/, but this does: /[a-z]/."
+    assert utf8_path_to_binary_regex("/[a-z]/").search(string).group(0) == b"/[a-z]/"
+
+
+def test_utf8_paths_to_single_binary_regex():
+    regex = utf8_paths_to_single_binary_regex(["/first/path", "/second/path", "/safe/[a-z]"])
+    # Match nothing
+    assert not regex.search(b"text /neither/first/path text /the/second/path text")
+
+    # Match first
+    string = b"contains both /first/path/subdir and /second/path/sub"
+    assert regex.search(string).group(0) == b"/first/path/subdir"
+
+    # Match second
+    string = b"contains both /not/first/path/subdir but /second/path/subdir"
+    assert regex.search(string).group(0) == b"/second/path/subdir"
+
+    # Match "unsafe" dir name
+    string = b"don't match /safe/a/path but do match /safe/[a-z]/file"
+    assert regex.search(string).group(0) == b"/safe/[a-z]/file"