The performance of professional tennis players in the four major Grand Slam tournaments has always been an important research topic, which advances the understanding of the current development of tennis. However, there is little known about the difference between higher-ranked and lower-ranked players considering match performance statistics. The study was aimed to explore the technical, tactical, and physical performance indicators that best discriminate seeded and non-seeded male players in Grand Slams. A total of 549 matches played by 189 individual players during 2015–2017 Grand Slam men’s singles were sampled, with corresponding match statistics gathered for each player observation, concerning players’ serving, returning, net point, break point, efficiency, and physical performance. The results showed that the seeded players outperformed the non-seeded players in serve and return, break point, net point, and efficiency-related indicators, while the following indicators contributed most to the separation of two player categories: serve and return of serve points won (%), ace (%), peak serve speed, net points won (%), break point per return game, break point saved, winner and unforced error ratio, and dominance ratio. The research findings evidenced the decreased competitive balance in men’s competition during Grand Slams due to a rank-based seeding system, whereas coaches could use the information to fine-tune the training benchmarks and match planning.