diff --git a/doc/source/whatsnew/v3.0.0.rst b/doc/source/whatsnew/v3.0.0.rst
index 126a5e10c0e85..69dd8ef49c526 100644
--- a/doc/source/whatsnew/v3.0.0.rst
+++ b/doc/source/whatsnew/v3.0.0.rst
@@ -1049,6 +1049,7 @@ Interval
 - Bug in :class:`Index`, :class:`Series`, :class:`DataFrame` constructors when given a sequence of :class:`Interval` subclass objects casting them to :class:`Interval` (:issue:`46945`)
 - Bug in :func:`interval_range` where start and end numeric types were always cast to 64 bit (:issue:`57268`)
 - Bug in :meth:`IntervalIndex.get_indexer` and :meth:`IntervalIndex.drop` when one of the sides of the index is non-unique (:issue:`52245`)
+- 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 b0472c70557e5..3e724b176b76d 100644
--- a/pandas/core/arrays/interval.py
+++ b/pandas/core/arrays/interval.py
@@ -420,6 +420,18 @@ def _ensure_simple_new_inputs(
 
         dtype = IntervalDtype(left.dtype, closed=closed)
 
+        # Check for mismatched signed/unsigned integer dtypes after casting
+        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}."
+            )
         return left, right, dtype
 
     @classmethod
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])