Simon Cameron was born on March 8, 1799, in Maytown, Pennsylvania. He was the third of eight children born to Charles Cameron, a very poor tailor, and Martha Pfoutz. After a move to Lewisburg where the family lived in squalid conditions, his father died. Cameron, who was only nine, was forced to consider how best to earn a living. Due to limited formal schooling, Cameron's reading and writing abilities were largely self-taught. Nevertheless, he soon became apprentice to a printer, Andrew Kennedy, of the Northumberland County Gazette, and he began honing his journalistic skills.

When Kennedy encountered financial difficulties and was forced to close his printing business, Cameron apprenticed himself to James Peacock, editor of the Republican, becoming assistant editor within two years. He then went to Washington, D.C. and obtained work with Gales and Seaton printers, who published the National Intelligencer and the Annals of Congress. In his twenties, Cameron diversified his publishing interests and began working in both printing and editing. His editorial position permitted him to take an active part in politics, while his growing reputation enabled him to become the state printer of Pennsylvania. This high profile position allowed Cameron to make helpful connections, such as his friendship with Governor J. Andrew Shulze. Shulze appointed Cameron adjutant general of Pennsylvania, a role he still held after Shulze's term in office ended. Cameron earned the nickname "General" from this position, a moniker that followed him for the rest of his life.

The capital and connections made from Cameron's publishing ventures allowed him to turn his attention to investment and development projects. In 1826, Cameron started building a section of the Pennsylvania Canal along the Susquehanna River. Six years later, Cameron was a commissioner for the Bank of Middletown. When it opened, he became a cashier. Cameron's salary increased due to his banking position, so he next took part in railroad development. He was a major player in the construction of the Lancaster and Harrisburg Railroad line, and he created and became president of the Northern Central Railroad, which connected central Pennsylvania to Baltimore, Maryland. This railroad, nicknamed the "Cameron road," became a major transportation route for soldiers and supplies during the Civil War.

As Cameron saw profits from his various business ventures grow, he became friends with more influential men, studied the mechanics of practical politics, and learned the give and take nature of campaigning. Cameron was chosen to represent President Jackson's interests in Pennsylvania during the president's campaign for re-election in 1836. In this position, Cameron was able to throw Pennsylvania's votes to Martin Van Buren for vice-president, rather than to William Wilkins, who had been the electoral choice leading up to the national convention. Pennsylvania newspapers were in an uproar, claiming that Cameron had misrepresented the people of Pennsylvania. Although this move angered the newspapers, it garnered the support of Jackson and Van Buren, two crucial allies for Cameron's burgeoning career in politics.

When James Buchanan resigned as a United States Senator in 1845, the Pennsylvania Legislature needed to find a new candidate to complete the remaining four years of his term. After balloting was conducted, Cameron won the position. Cameron served out Buchanan's term, but many Democrats believed he had manipulated the 1844 election so he could become senator. Thus, when the 1848 election approached, Cameron faced the ugly reality that he had managed to alienate many members of his own party. Without their support, Cameron was not re-elected and withdrew from politics for a time period.

Cameron began campaigning for the 1850 election, but he was met with resistance from his own party, who thought he was "a dishonest man, not qualified by education or talents for honorable position, and destitute of all claims for respect, either public or private." This strongly-held grudge, stemming from his first term in the Senate, caused Cameron to forge alliances with Whig party members. Without the support of the Democrats, however, Cameron was unable to reclaim his senatorial seat, despite being what the New York Daily Times called a "shrewd party manager." In 1857, after switching to the newly-created Republican party, Cameron succeeded in winning a Senate seat. Thaddeus Stevens, a congressman integral to the founding of the Republican Party, called Cameron's return to the Senate the result of "wholesale private bribery," but these allegations could not be proven.

In preparation for the 1860 presidential election, the Republican party held its convention in Chicago, Illinois, to discuss potential candidates. Cameron was on the list of men considered for the nomination, although he professed he did not expect to be chosen. Cameron lent support to one of the other candidates, William H. Seward of New York. As the convention approached, opposition against Seward increased, and Cameron's friends suggested that Abraham Lincoln of Illinois would be a better candidate to endorse. At the convention, Seward, Cameron, and Lincoln were all were nominated as candidates, but after several rounds of balloting, Lincoln received the votes necessary to become the Republican party's choice for president. Afterwards, Cameron made a speech in Harrisburg in which he fully recommended Lincoln as the party candidate.

After Lincoln was elected to the presidency, Cameron's friends and allies pushed Lincoln to include Cameron in his cabinet. For his part, Cameron did not seem particularly willing to trade his senatorial position for what he believed would be a subordinate place in Lincoln's cabinet. Meanwhile, Cameron's adversaries convinced Lincoln that Cameron would not be fit for a cabinet position, and Lincoln privately asked Cameron to withdraw from consideration. Never one to back down from a challenge, Cameron refused to concede and waited for Lincoln to publicly withdraw the offer. Beset with allegations against Cameron's personal and political character on one side, and with glowing recommendations of his fitness for the position on the other, Lincoln was in a bind. To extricate himself from the situation, he asked for documented proof of the allegations against Cameron, but Cameron's opponents would produce none. With nothing but hearsay and rumors to validate the slander against Cameron, Lincoln pressed the senator to accept the Secretary of War position, believing Cameron could do less damage there than as Secretary of the Treasury. Although Cameron would have preferred Secretary of the Treasury and its patronage positions, he nonetheless accepted the Lincoln's offer.

With the Civil War looming, Cameron's position as Secretary of War gained new importance. Cameron's duty to organize and equip thousands of soldiers gave him a position of authority. He ultimately wielded this power ineffectively, awarding positions within the department to his friends and supporters. Cameron also wasted money on unneeded and inferior supplies, and he awarded commissions in the Army. Contrary to Lincoln's beliefs, Cameron thought slaves who escaped to free territories should be freed themselves. Without Lincoln's knowledge, Cameron sent a letter to several newspapers demanding a slave army. Cameron argued that employing slaves in the army "may be useful withheld from the enemy, it lessens his military resources." When Lincoln discovered Cameron's treachery, he recommended that Cameron accept a position as the United States Minister to Russia. In defense of his actions as Secretary of War, Cameron wrote, "I have done my best. It is impossible, in the direction of operations so extensive, but that some mistakes happen and some complications and complaints arise."

In 1862, after censure from the House of Representatives for his short term as the Secretary of War, Cameron traveled to Europe to fulfill his new duties. Unhappy with this position, he returned to America within the year. He was again elected to the Senate in 1867 and served until 1877. During this time, he served as the chairman of the Committee on Agriculture, the Committee on Foreign Relations, and the Committee on Public Buildings and Grounds. Cameron also managed to get his 1862 censure from the House of Representatives rescinded, an achievement that caused him to be in "excellent spirits."

Cameron, who was friends with Ulysses S. Grant, managed to get his son, James Donald Cameron, the position of Secretary of War in the president's cabinet. When his son was in danger of losing this position, Cameron made a deal to retire, which enabled his son to succeed him in Congress. Just when the New York Times believed Cameron had "turned his back upon the world, fore-swore politics, and resolved to live cleanly," he "return[ed] to politics more than ever" by becoming the United States Minister to England. During the next twelve years, Cameron traveled extensively in Europe.

Cameron died on June 26, 1889, in Donegal Springs, Pennsylvania.