The only officially licensed baseball game from a third-party publisher in 2006, Major League Baseball 2K6 for PSP retains many of the features found in the console versions. The game introduces a timing-based pitching system that involves tapping a button at specific moments to determine how close the ball will reach its intended target. Fielding now takes into account an athlete's momentum, allowing players to nudge or push the analog stick to jog or run. Stronger, riskier throws are also possible by applying pressure to the face buttons, while collisions can occur on the base paths or in the field. The experienced broadcasting team of Jon Miller and Joe Morgan handle commentary duties for the handheld version as well.
The PSP game includes Inside Edge scouting data to mimic real-life tendencies of the hitters and hurlers in the dugouts and bullpens. By spending a specific number of Inside Edge "points" during a game, players can learn where to pitch a particular hitter or determine the likelihood a pitcher is going to bring the heat in certain situations. In addition to the standard season, franchise, and playoff game modes, Major League Baseball 2K6 includes the international teams and all-star lineups from the inaugural World Baseball Classic. Exclusive to the PSP is a Home Run Derby mode that follows a season-style format, where players take on the top sluggers from each team in multiple contests. Would-be managers can also seek out opponents online using the handheld's Infrastructure Mode.