Simon was born in late November, c. 2490 to Gabriel and Regan Tam, and was born and raised on Osiris, a Core World planet with major Alliance ties.

Due to an arrangement with his father when he was young, where Simon would receive a dedicated source box for access to the Cortex (similar to the Internet) in exchange for becoming a brilliant doctor, Simon eventually entered medical school c. 2507. In fact, due to Simon being considered practically gifted, he was accepted to the best Medical Academy, or "MedAcad," on Osiris. Simon graduated in the top 3% of his class, and promptly moved onto a medical internship, which he completed in a mere eight months (as opposed to a year), and is licensed to practice medicine.

Simon later tells Kaylee Frye, engineer of Serenity, that after he and his fellow doctors officially became surgeons, they imbibed quite a large amount of sake, and ended up naked on a statue of Hippocrates. There are rumours that Simon began singing the National Anthem, and he either talked or paid his way out of the Alliance telling his father. Simon admits that he is quite "fuzzy on details" regarding this story.

From there, he became a resident trauma surgeon on one of the major hospitals in Capital City, Osiris.

Around this time, the Tam family was made aware of an elite Alliance-sponsored school called The Academy that their youngest daughter, River could attend. Simon began receiving notes from River a few months into her schooling, littered with spelling errors and mentions of parties and families that did not exist. Eventually, Simon realizes that River is writing in code, asking him to rescue her, though when he informs his parents of this, they dismiss it as paranoia (as seen in "Safe").

Due to Simon's intense attachment to River, however, he continues a quest to find and bring her out of the Academy, even going to lengths to enter Illegal Blackout Zones – although these are never exactly explained – and arrested, much to the shame of his father and family. Eventually, after two years of searching, he is contacted by an underground group that said they could rescue River and deliver her to Simon, should he be able to pay enough.

Simon manages to break into the Academy disguised as a uniformed official of the Alliance government and asks questions of Dr. Mathias about River’s treatment. Simon activates a hidden stun grenade and releases River. They then run to the window of an elevator shaft, break through, and a ship overhead releases a raft that they ride up to safety. This was all caught on the security cameras of the Academy (as seen in Serenity).

There is a discrepancy regarding Simon's role in this endeavour, as the film and the series offer slightly conflicting views on how exactly River is released from the Academy.

When the Alliance learns of River's rescue, they promptly freeze all of Simon's monetary accounts, leaving him with nothing but his medkit, and put out a warrant for the arrest of both Simon and River, labelling them as fugitives (as mentioned in "Safe" and "Ariel'").

Simon eventually makes it to Persephone, a planet slightly outside the Core, where, at the Eavesdown Docks, he decides to board Serenity, bringing with him a large case that is eventually revealed to be River, cryogenically frozen.