He played college basketball for the UCLA Bruins, earning second-team all-conference honors in the Pac-12 as a junior in 2015–16.

Hamilton grew up in the Los Angeles area, where he was among the top high school players.

As a senior in 2013, he captured all-state honors in California, and was nationally recognized as a McDonald's All-American.

Hamilton was required to sit out his freshman year after UTEP would not grant him a release from his commitment.

[5] As a junior, Hamilton was voted third-team all-state by Cal-Hi Sports after averaging 24.3 points, 9.6 rebounds, and 5.4 assists and leading his team to the SoCal Div.

[3] In his senior year, he averaged 22.1 points, 5.7 rebounds and 4.5 assists per game, and St. John Bosco captured a CIF Southern Section Class 3A title, its first since 2003.

However, he later requested a release, citing a desire to attend a school closer to home, preferably in Los Angeles, to be with his grandmother, who was sick with a heart condition.

His younger brother, Daniel chose to go to school at UCONN even though his grandmother was sick, causing many to speculate that Isaac's reasoning was false.

Three of UCLA's top four scorers from the previous year had moved on to play professionally in the National Basketball Association (NBA).

[15][16] On November 28, 2014, he scored a team-high 21 points at the Battle 4 Atlantis, helping UCLA salvage a win in the seventh-place game.

[17] Just a day earlier, he had missed all six of his shots and committed seven turnovers due to poor decisions and bad passes in a loss to North Carolina.

[14] Towards the middle of the season, Hamilton at times would again assume the point guard role for the Bruins, and Alford would shift to being a scorer.

[16] In the quarterfinals of the 2015 Pac-12 tournament, Hamilton made 13 of 17 field goal attempts to score a career-high 36 points in a 96–70 win over USC.

His grandmother had died just four days earlier, but he decided to play as the Bruins were still fighting to qualify for the NCAA tournament.

[19][20] Hamilton opened 2015–16 as part of a three-guard lineup, with Alford and freshman Aaron Holiday sharing most of the point guard responsibilities.

[27] After a month-long shooting slump,[33] during which he never divulged a pulled back muscle that required a doctor's visit,[34] Hamilton made a UCLA record nine three-pointers against Arizona State to tie the mark held by Alford and Jason Kapono.