diff --git a/pandas/_libs/index.pyx b/pandas/_libs/index.pyx
index 31b507e9b7800..cdb53e0e838e9 100644
--- a/pandas/_libs/index.pyx
+++ b/pandas/_libs/index.pyx
@@ -87,11 +87,7 @@ cdef class IndexEngine:
             values = self.values
 
             self._check_type(val)
-            try:
-                loc = _bin_search(values, val)  # .searchsorted(val, side='left')
-            except TypeError:
-                # GH#35788 e.g. val=None with float64 values
-                raise KeyError(val)
+            loc = self._searchsorted_left(val)
             if loc >= len(values):
                 raise KeyError(val)
             if values[loc] != val:
@@ -110,6 +106,17 @@ cdef class IndexEngine:
             # GH#41775 OverflowError e.g. if we are uint64 and val is -1
             raise KeyError(val)
 
+    cdef Py_ssize_t _searchsorted_left(self, val) except? -1:
+        """
+        See ObjectEngine._searchsorted_left.__doc__.
+        """
+        try:
+            loc = self.values.searchsorted(val, side="left")
+        except TypeError as err:
+            # GH#35788 e.g. val=None with float64 values
+            raise KeyError(val)
+        return loc
+
     cdef inline _get_loc_duplicates(self, object val):
         # -> Py_ssize_t | slice | ndarray[bool]
         cdef:
@@ -373,6 +380,11 @@ cdef class IndexEngine:
 
 
 cdef Py_ssize_t _bin_search(ndarray values, object val) except -1:
+    # GH#1757 ndarray.searchsorted is not safe to use with array of tuples
+    #  (treats a tuple `val` as a sequence of keys instead of a single key),
+    #  so we implement something similar.
+    # This is equivalent to the stdlib's bisect.bisect_left
+
     cdef:
         Py_ssize_t mid = 0, lo = 0, hi = len(values) - 1
         object pval
@@ -405,6 +417,15 @@ cdef class ObjectEngine(IndexEngine):
     cdef _make_hash_table(self, Py_ssize_t n):
         return _hash.PyObjectHashTable(n)
 
+    cdef Py_ssize_t _searchsorted_left(self, val) except? -1:
+        # using values.searchsorted here would treat a tuple `val` as a sequence
+        #  instead of a single key, so we use a different implementation
+        try:
+            loc = _bin_search(self.values, val)
+        except TypeError as err:
+            raise KeyError(val) from err
+        return loc
+
 
 cdef class DatetimeEngine(Int64Engine):
 
diff --git a/pandas/tests/indexes/base_class/test_indexing.py b/pandas/tests/indexes/base_class/test_indexing.py
index 654f5a89f1828..d961f3f416bda 100644
--- a/pandas/tests/indexes/base_class/test_indexing.py
+++ b/pandas/tests/indexes/base_class/test_indexing.py
@@ -1,6 +1,7 @@
 import numpy as np
 import pytest
 
+import pandas as pd
 from pandas import Index
 import pandas._testing as tm
 
@@ -36,3 +37,22 @@ def test_get_indexer_non_unique_dtype_mismatch(self):
         indexes, missing = Index(["A", "B"]).get_indexer_non_unique(Index([0]))
         tm.assert_numpy_array_equal(np.array([-1], dtype=np.intp), indexes)
         tm.assert_numpy_array_equal(np.array([0], dtype=np.intp), missing)
+
+
+class TestGetLoc:
+    @pytest.mark.slow  # to_flat_index takes a while
+    def test_get_loc_tuple_monotonic_above_size_cutoff(self):
+        # Go through the libindex path for which using
+        # _bin_search vs ndarray.searchsorted makes a difference
+
+        lev = list("ABCDEFGHIJKLMNOPQRSTUVWXYZ")
+        dti = pd.date_range("2016-01-01", periods=100)
+
+        mi = pd.MultiIndex.from_product([lev, range(10 ** 3), dti])
+        oidx = mi.to_flat_index()
+
+        loc = len(oidx) // 2
+        tup = oidx[loc]
+
+        res = oidx.get_loc(tup)
+        assert res == loc
diff --git a/pandas/tests/indexes/numeric/test_indexing.py b/pandas/tests/indexes/numeric/test_indexing.py
index 8f113491dad60..dae8a3340bcd2 100644
--- a/pandas/tests/indexes/numeric/test_indexing.py
+++ b/pandas/tests/indexes/numeric/test_indexing.py
@@ -152,6 +152,14 @@ def test_get_loc_float_index_nan_with_method(self, vals, method):
             with tm.assert_produces_warning(FutureWarning, match="deprecated"):
                 idx.get_loc(np.nan, method=method)
 
+    @pytest.mark.parametrize("dtype", ["f8", "i8", "u8"])
+    def test_get_loc_numericindex_none_raises(self, dtype):
+        # case that goes through searchsorted and key is non-comparable to values
+        arr = np.arange(10 ** 7, dtype=dtype)
+        idx = Index(arr)
+        with pytest.raises(KeyError, match="None"):
+            idx.get_loc(None)
+
 
 class TestGetIndexer:
     def test_get_indexer(self):