diff --git a/qiskit_addon_aqc_tensor/ansatz_generation/from_connectivity.py b/qiskit_addon_aqc_tensor/ansatz_generation/from_connectivity.py
index 9b7391d..51c91e7 100644
--- a/qiskit_addon_aqc_tensor/ansatz_generation/from_connectivity.py
+++ b/qiskit_addon_aqc_tensor/ansatz_generation/from_connectivity.py
@@ -15,6 +15,7 @@
 
 from __future__ import annotations
 
+import logging
 from typing import Sequence
 
 import numpy as np
@@ -25,9 +26,15 @@
     QuantumCircuit,
 )
 from qiskit.circuit.library import UnitaryGate
+from qiskit.compiler import transpile
+from qiskit.exceptions import QiskitError
 from qiskit.quantum_info import Operator
 from qiskit.synthesis import OneQubitEulerDecomposer, TwoQubitWeylDecomposition
 
+logger = logging.getLogger(__name__)
+# We'd like the user to actually see warnings from this module by default
+logger.setLevel(logging.WARNING)
+
 
 class AnsatzBlock(Gate):
     """Ansatz block.
@@ -300,7 +307,21 @@ def perform_separation(q0: int, q1: int):
         partner[q1] = None
         couple_qc = couples[q0, q1]
         mat = Operator(couple_qc).data
-        d = TwoQubitWeylDecomposition(mat)
+        try:
+            d = TwoQubitWeylDecomposition(mat)
+        except QiskitError as exc:
+            # Try again with the transpiled circuit.  See
+            # https://github.com/Qiskit/qiskit-addon-aqc-tensor/pull/100
+            logger.warning(
+                "M2 diagonalization has failed with the following non-fatal exception:",
+                exc_info=exc,
+            )
+            logger.warning(
+                "Trying M2 diagonalization again with transpiled 2-qubit circuit.",
+            )
+            couple_qc = transpile(couple_qc, basis_gates=["cx", "rx", "ry", "rz"])
+            mat = Operator(couple_qc).data
+            d = TwoQubitWeylDecomposition(mat)
         singles[q0] = [UnitaryGate(d.K1r)]
         singles[q1] = [UnitaryGate(d.K1l)]
         fp01 = free_params[q0, q1]
diff --git a/releasenotes/notes/TwoQubitWeylDecomposition-fix-52d4b0e63a12f346.yaml b/releasenotes/notes/TwoQubitWeylDecomposition-fix-52d4b0e63a12f346.yaml
new file mode 100644
index 0000000..4d1f092
--- /dev/null
+++ b/releasenotes/notes/TwoQubitWeylDecomposition-fix-52d4b0e63a12f346.yaml
@@ -0,0 +1,12 @@
+---
+fixes:
+  - |
+    This adds a workaround for an issue sometimes encountered when calling :class:`~qiskit.synthesis.TwoQubitWeylDecomposition` inside
+    :func:`.generate_ansatz_from_circuit`. Sometimes an error is thrown despite the input matrix
+    being unitary to numerical precision, and returning :meth:`~qiskit.quantum_info.Operator.is_unitary()`` as ``True``. This is
+    an ongoing issue in qiskit, see `https://github.com/Qiskit/qiskit/issues/4159` for more details.
+
+    With this workaround, any time the error is encountered, it will retry by transpiling the two-qubit circuit (from which the
+    matrix is derived) prior to passing the matrix to :class:`~qiskit.synthesis.TwoQubitWeylDecomposition`. It should
+    be noted that this is does not fix the root issue, and is not guaranteed to always work, but has
+    been observed to work for some instances.
diff --git a/test/ansatz_generation/test_from_connectivity.py b/test/ansatz_generation/test_from_connectivity.py
index 9e3a4f1..e90df6f 100644
--- a/test/ansatz_generation/test_from_connectivity.py
+++ b/test/ansatz_generation/test_from_connectivity.py
@@ -91,3 +91,14 @@ def test_idle_qubit(self):
         qc.x(0)
         _, initial_parameters = generate_ansatz_from_circuit(qc)
         assert len(initial_parameters) == 3
+
+    def test_large_circuit_no_two_qubit_weyl_decomposition_error(self):
+        qc = QuantumCircuit(50)
+
+        for _ in range(10):
+            for i in range(0, 50, 2):
+                qc.cx(i, i + 1)
+            for i in range(1, 49, 2):
+                qc.cx(i, i + 1)
+
+        _, _ = generate_ansatz_from_circuit(qc, qubits_initially_zero=True)