Measuring in at 75 miles (120km), it weaves its way from its source in the Cambrian Mountains above Llyn Brianne reservoir to the sea at Carmarthen Bay.
Discover the Tywi Valley for yourself by following the river, from source to sea, taking in some of the country's most stunning attractions en route. We've put together a four-day itinerary that takes you past the highlights. All that's left is for you to decide if you want to do the whole thing or dip in and out of the river's path as you please.
Day 1: Cambrian Mountains to Llandovery
Start the day by finding the source of the river in the Cambrian Mountains. It begins on the lower slopes of Crug Gynan and flows at speed for six miles before reaching Llyn Brianne, a huge man-made reservoir that supplies water to much of South Wales.
Just south of Llyn Brianne is Gwenffrwd Dinas, a 600-hectare RSPB nature reserve. Here, there's a pretty three-mile trail along the river, with an optional (and steep) detour that leads to the Twm Sion Cati's cave – a place where, according to folklore, the Welsh Robin Hood would hide to avoid capture.
Overnight: Llandovery, a small market town with the remains of a castle and numerous rural pubs.
Day 2: Carreg Cennen, Llandeilo and Dinefwr
From Llandovery, it's about an hour's drive to the second town on the itinerary: Llandeilo. Once there, two castle-shaped options open up.
Carreg Cennen Castle, voted the most romantic ruin in Wales by readers of Countryfile magazine, sits atop of a limestone crag to the south east of Llandeilo. Being 90m (300ft) above the River Cennen below, it's a great spot for views across the wild Carmarthenshire countryside. There's a cave, a vaulted passage in the cliff face and a real sense of peaceful solitude.
Dinefwr Park and Castle is ideal for a lazy afternoon of meandering. Within the grounds are a national nature reserve, an historic house with a museum and an 18th-century landscape park with a medieval deer park. During spring, its lawns and wooded areas are strewn with daffodils and bluebells. There are also the ruins of a 12th century castle, demonstrating the long history of the site.
Overnight: Llandeilo, where you can shop for locally made chocolate at Heavenly.
Day 3: Aberglasney to National Botanic Garden
Being in such a naturally beautiful area, it comes as no surprise that there are yet more glorious parks and mighty castles to check out further along the river.
Aberglasney Gardens is the first stop of the day. Dating back to 1477, Aberglasney was in quite a state near the turn of the second millennium. Thanks to a major campaign to save the site, it underwent extensive restoration between 1995 and 2013, with minor works continuing to this day. Despite this long history of repair, it is a handsome place with 10 acres of ancient formal gardens and rare plants.
Dryslwyn Castle, a 13th century fortress on an isolated hill, is just five minutes' drive from Aberglasney, and is worthy of a quick visit before you progress to Paxton's Tower in Llantharne. The latter was built over 200 years ago. While it looks like it would be the site of an epic battle, it is simply an impressive folly designed to commemorate Nelson. Its 360-degree views of the surrounding area are fantastic on a clear day.
For lunch, head to the nearby Wright's Food Emporium to refuel on sandwiches stacked with locally sourced produce and a slice of homemade cake. Then, it's on to the National Botanic Garden of Wales, a 568-acre parkland with its horticultural displays, meadows full of flowers, calm lakes, water sculptures, bees, boulders and lots of walking routes through nature. Inside its domed Great Glasshouse – the world's largest single-span glasshouse – is a Mediterranean-inspired landscape with a deep ravine, a lake, an olive grove and waterfalls, while the Japanese Garden looks as though it was lifted straight out of Asia.
Day 4: Llansteffan Castle and ferry crossing
Just like the River Tywi, the trip draws to an end in the Welsh village of Llansteffan. From the centre, walk up to Llansteffan Castle. It was built in the 1100s on top of a well-defined headland and has superb views over the sand flats of the Twyi estuary.
To get even closer to the river, climb aboard the Carmarthen Bay ferry's '1 Hour Towy River Cruise' from Llansteffan. The amphibious boat follows the river from Llangain down to St Ishmaels, sharing nuggets of local trivia and giving you ample opportunities to spot otters, seals and rare birds in the water and on the river banks.