Guildford pushed Leander all the way for the crown, but the city side sealed the win with some stunning relay swimming at the end.
Leander scored 362 points, with Guildford second on 342 points and Millfield third with 330.
The only year Plymouth have not won the league since 2008 was in 2011 when the trophy went to Stockport.
Western League champions Leander, who had international stars Ruta Meilutyte, Ben Proud and Antony James among their team, broke a number of meet records, while Laura Stephens was named most improved under-15 girl and Sam Dailley most improved under-13 boy.
Stephens, Dailley, Meilutyte, Proud and James were all among Leander’s individual winners on the day, as was Oscar Brain, while there were second-placed finishes for the likes of Joe Hulme, Charlotte Atkinson, Emma England, Connor Robinson and Shauna Lee.