diff --git a/doc/hardware/peripherals/uart.rst b/doc/hardware/peripherals/uart.rst
index b190dcbeea0..42906bca6fa 100644
--- a/doc/hardware/peripherals/uart.rst
+++ b/doc/hardware/peripherals/uart.rst
@@ -28,6 +28,15 @@ The Asynchronous API allows to read and write data in the background using DMA
 without interrupting the MCU at all. However, the setup is more complex
 than the other methods.
 
+.. warning::
+
+   Interrupt-driven API and the Asynchronous API should NOT be used at
+   the same time, since both APIs require hardware interrupts to function
+   properly, using the callbacks for both APIs would result in interference
+   between each other. :kconfig:option:`CONFIG_UART_EXCLUSIVE_API_CALLBACKS`
+   is enabled by default so that only the callbacks associated with one API
+   is active at a time.
+
 
 Configuration Options
 *********************
diff --git a/drivers/serial/Kconfig b/drivers/serial/Kconfig
index 405fda7d074..a803c152919 100644
--- a/drivers/serial/Kconfig
+++ b/drivers/serial/Kconfig
@@ -76,6 +76,21 @@ config UART_INTERRUPT_DRIVEN
 	  This option enables interrupt support for UART allowing console
 	  input and other UART based drivers.
 
+config UART_EXCLUSIVE_API_CALLBACKS
+	bool "Use exclusive callbacks for multiple APIs"
+	depends on UART_ASYNC_API && UART_INTERRUPT_DRIVEN
+	default y
+	help
+	  When multiple set of APIs support callbacks, enabling this
+	  option will result in only the callbacks of one set of API
+	  being active at a time. Setting a new callback to one set of
+	  API will remove callbacks to other set of APIs. For example,
+	  calling uart_callback_set() would disable the callback
+	  previously set via uart_irq_callback_set().
+
+	  Says yes unless you are absolutely sure you know what you are
+	  doing and promise not to file bug when things do not work out.
+
 config UART_LINE_CTRL
 	bool "Serial Line Control API"
 	help
diff --git a/drivers/serial/uart_esp32.c b/drivers/serial/uart_esp32.c
index 380226dcfe6..a1054ba7d85 100644
--- a/drivers/serial/uart_esp32.c
+++ b/drivers/serial/uart_esp32.c
@@ -435,6 +435,11 @@ static void uart_esp32_irq_callback_set(const struct device *dev, uart_irq_callb
 
 	data->irq_cb = cb;
 	data->irq_cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async.cb = NULL;
+	data->async.user_data = NULL;
+#endif
 }
 
 #endif /* CONFIG_UART_INTERRUPT_DRIVEN */
@@ -662,6 +667,11 @@ static int uart_esp32_async_callback_set(const struct device *dev, uart_callback
 	data->async.cb = callback;
 	data->async.user_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->irq_cb = NULL;
+	data->irq_cb_data = NULL;
+#endif
+
 	return 0;
 }
 
diff --git a/drivers/serial/uart_mcux_flexcomm.c b/drivers/serial/uart_mcux_flexcomm.c
index 041f690317d..4332b20cb91 100644
--- a/drivers/serial/uart_mcux_flexcomm.c
+++ b/drivers/serial/uart_mcux_flexcomm.c
@@ -279,6 +279,11 @@ static void mcux_flexcomm_irq_callback_set(const struct device *dev,
 
 	data->irq_callback = cb;
 	data->irq_cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async_callback = NULL;
+	data->async_cb_data = NULL;
+#endif
 }
 #endif /* CONFIG_UART_INTERRUPT_DRIVEN */
 
@@ -400,6 +405,12 @@ static int mcux_flexcomm_uart_callback_set(const struct device *dev,
 	data->async_callback = callback;
 	data->async_cb_data = user_data;
 
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->irq_callback = NULL;
+	data->irq_cb_data = NULL;
+#endif
+
 	return 0;
 }
 
diff --git a/drivers/serial/uart_mcux_lpuart.c b/drivers/serial/uart_mcux_lpuart.c
index cdafa42d585..e1fe23ea322 100644
--- a/drivers/serial/uart_mcux_lpuart.c
+++ b/drivers/serial/uart_mcux_lpuart.c
@@ -370,6 +370,11 @@ static void mcux_lpuart_irq_callback_set(const struct device *dev,
 
 	data->callback = cb;
 	data->cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async.user_callback = NULL;
+	data->async.user_data = NULL;
+#endif
 }
 
 #endif /* CONFIG_UART_INTERRUPT_DRIVEN */
@@ -661,6 +666,11 @@ static int mcux_lpuart_callback_set(const struct device *dev, uart_callback_t ca
 	data->async.user_callback = callback;
 	data->async.user_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->callback = NULL;
+	data->cb_data = NULL;
+#endif
+
 	return 0;
 }
 
diff --git a/drivers/serial/uart_nrfx_uart.c b/drivers/serial/uart_nrfx_uart.c
index 77efdd0050a..96cb190a487 100644
--- a/drivers/serial/uart_nrfx_uart.c
+++ b/drivers/serial/uart_nrfx_uart.c
@@ -405,6 +405,11 @@ static int uart_nrfx_callback_set(const struct device *dev,
 	uart0_cb.callback = callback;
 	uart0_cb.user_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	irq_callback = NULL;
+	irq_cb_data = NULL;
+#endif
+
 	return 0;
 }
 
@@ -923,6 +928,11 @@ static void uart_nrfx_irq_callback_set(const struct device *dev,
 	(void)dev;
 	irq_callback = cb;
 	irq_cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	uart0_cb.callback = NULL;
+	uart0_cb.user_data = NULL;
+#endif
 }
 
 /**
diff --git a/drivers/serial/uart_nrfx_uarte.c b/drivers/serial/uart_nrfx_uarte.c
index 047405b84c0..16877328e5f 100644
--- a/drivers/serial/uart_nrfx_uarte.c
+++ b/drivers/serial/uart_nrfx_uarte.c
@@ -937,6 +937,11 @@ static int uarte_nrfx_callback_set(const struct device *dev,
 	data->async->user_callback = callback;
 	data->async->user_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->int_driven->cb = NULL;
+	data->int_driven->cb_data = NULL;
+#endif
+
 	return 0;
 }
 
@@ -1675,6 +1680,11 @@ static void uarte_nrfx_irq_callback_set(const struct device *dev,
 
 	data->int_driven->cb = cb;
 	data->int_driven->cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async->user_callback = NULL;
+	data->async->user_data = NULL;
+#endif
 }
 #endif /* UARTE_INTERRUPT_DRIVEN */
 
diff --git a/drivers/serial/uart_sam0.c b/drivers/serial/uart_sam0.c
index 82676b4f85b..4f4407bdca9 100644
--- a/drivers/serial/uart_sam0.c
+++ b/drivers/serial/uart_sam0.c
@@ -935,6 +935,11 @@ static void uart_sam0_irq_callback_set(const struct device *dev,
 
 	dev_data->cb = cb;
 	dev_data->cb_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	dev_data->async_cb = NULL;
+	dev_data->async_cb_data = NULL;
+#endif
 }
 #endif
 
@@ -949,6 +954,11 @@ static int uart_sam0_callback_set(const struct device *dev,
 	dev_data->async_cb = callback;
 	dev_data->async_cb_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	dev_data->cb = NULL;
+	dev_data->cb_data = NULL;
+#endif
+
 	return 0;
 }
 
diff --git a/drivers/serial/uart_stm32.c b/drivers/serial/uart_stm32.c
index 45a16e9e893..23be4a9138c 100644
--- a/drivers/serial/uart_stm32.c
+++ b/drivers/serial/uart_stm32.c
@@ -904,6 +904,11 @@ static void uart_stm32_irq_callback_set(const struct device *dev,
 
 	data->user_cb = cb;
 	data->user_data = cb_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async_cb = NULL;
+	data->async_user_data = NULL;
+#endif
 }
 
 #endif /* CONFIG_UART_INTERRUPT_DRIVEN */
@@ -1125,6 +1130,11 @@ static int uart_stm32_async_callback_set(const struct device *dev,
 	data->async_cb = callback;
 	data->async_user_data = user_data;
 
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->user_cb = NULL;
+	data->user_data = NULL;
+#endif
+
 	return 0;
 }
 
diff --git a/drivers/serial/uart_xmc4xxx.c b/drivers/serial/uart_xmc4xxx.c
index 278e7bcfb10..40e33b9fa45 100644
--- a/drivers/serial/uart_xmc4xxx.c
+++ b/drivers/serial/uart_xmc4xxx.c
@@ -360,6 +360,11 @@ static void uart_xmc4xxx_irq_callback_set(const struct device *dev,
 
 	data->user_cb = cb;
 	data->user_data = user_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->async_cb = NULL;
+	data->async_user_data = NULL;
+#endif
 }
 
 #define NVIC_ISPR_BASE 0xe000e200u
@@ -599,6 +604,12 @@ static int uart_xmc4xxx_async_callback_set(const struct device *dev, uart_callba
 
 	data->async_cb = callback;
 	data->async_user_data = user_data;
+
+#if defined(CONFIG_UART_EXCLUSIVE_API_CALLBACKS)
+	data->user_cb = NULL;
+	data->user_data = NULL;
+#endif
+
 	return 0;
 }