diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index f91d40c4d9ea9..09353a0436697 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -958,7 +958,7 @@ Interval
 ^^^^^^^^
 - :meth:`Index.is_monotonic_decreasing`, :meth:`Index.is_monotonic_increasing`, and :meth:`Index.is_unique` could incorrectly be ``False`` for an ``Index`` created from a slice of another ``Index``. (:issue:`57911`)
 - Bug in :func:`interval_range` where start and end numeric types were always cast to 64 bit (:issue:`57268`)
--
+- Construction of :class:`IntervalArray` and :class:`IntervalIndex` from arrays with mismatched signed/unsigned integer dtypes (e.g., ``int64`` and ``uint64``) now raises a :exc:`TypeError` instead of proceeding silently. (:issue:`55715`)
 
 Indexing
 ^^^^^^^^
diff --git a/pandas/core/arrays/interval.py b/pandas/core/arrays/interval.py
index 8d13e76c57e4f..392a3a0c0b6c1 100644
--- a/pandas/core/arrays/interval.py
+++ b/pandas/core/arrays/interval.py
@@ -536,6 +536,19 @@ def from_arrays(
         left = _maybe_convert_platform_interval(left)
         right = _maybe_convert_platform_interval(right)
 
+        # Check for mismatched signed/unsigned integer dtypes
+        left_dtype = left.dtype
+        right_dtype = right.dtype
+        if (
+            left_dtype.kind in "iu"
+            and right_dtype.kind in "iu"
+            and left_dtype.kind != right_dtype.kind
+        ):
+            raise TypeError(
+                f"Left and right arrays must have matching signedness. "
+                f"Got {left_dtype} and {right_dtype}."
+            )
+
         left, right, dtype = cls._ensure_simple_new_inputs(
             left,
             right,
diff --git a/pandas/tests/indexes/interval/test_interval.py b/pandas/tests/indexes/interval/test_interval.py
index 006a06e529971..b302e865eebd1 100644
--- a/pandas/tests/indexes/interval/test_interval.py
+++ b/pandas/tests/indexes/interval/test_interval.py
@@ -882,6 +882,14 @@ def test_is_all_dates(self):
         assert not year_2017_index._is_all_dates
 
 
+def test_from_arrays_mismatched_signedness_raises():
+    # GH 55715
+    left = np.array([0, 1, 2], dtype="int64")
+    right = np.array([1, 2, 3], dtype="uint64")
+    with pytest.raises(TypeError, match="matching signedness"):
+        IntervalIndex.from_arrays(left, right)
+
+
 def test_dir():
     # GH#27571 dir(interval_index) should not raise
     index = IntervalIndex.from_arrays([0, 1], [1, 2])